Diels-alder reactions of (E)-2-styrylquinolin-4(1H)-ones with N-methylmaleimide: New syntheses of acridin-9(10H)-ones

Article abstract of DOI:10.1055/s-0031-1290600

New syntheses of acridin-9(10H)-ones were developed. One involves a two-step transformation, namely the Diels-Alder -reactions of (E)-1-methyl-2-styrylquinolin-4(1H)-ones with N-methylmaleimide in refluxing toluene, followed by oxidation of the formed adducts. The second consists in an one-pot procedure using 1,2,4-trichlorobenzene as solvent at 180 C. The effect of microwave irradition and Lewis acid catalysts in these cycloaddition -reactions was also investigated. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290600

LETTER
889
Diels–Alder Reactions of (E)-2-Styrylquinolin-4(1H)-ones
with N-Methylmaleimide: New Syntheses of Acridin-9(10H)-ones
New
S
yntheses of
n
A
cridin-9(10
d
H
)-one
s
reia I. S. Almeida, Vera L. M. Silva, Artur M. S. Silva,* Diana C. G. A. Pinto, José A. S. Cavaleiro
Department of Chemistry, QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370714; E-mail: artur.silva@ua.pt
Received 26 November 2011
(13–25%), due to a high degradation of the reaction mix-
ture. In spite of this, small amounts of 4a–c (2–5%) were
also obtained (Scheme 1, Table 1). Trying to reduce the
referred high degradation, the Diels–Alder reactions were
Abstract: New syntheses of acridin-9(10H)-ones were developed.
One involves a two-step transformation, namely the Diels–Alder
reactions of (E)-1-methyl-2-styrylquinolin-4(1H)-ones with N-me-
thylmaleimide in refluxing toluene, followed by oxidation of the
formed adducts. The second consists in an one-pot procedure using carried out in 1,2,4-trichlorobenzene at 180 °C, until com-
1,2,4-trichlorobenzene as solvent at 180 °C. The effect of micro-
wave irradition and Lewis acid catalysts in these cycloaddition
reactions was also investigated.
plete consumption of the starting materials 1a–c (42–48 h,
Scheme 1). Under these conditions the in situ oxidation of
3a–c was observed, and compounds 4a–c9 were obtained
Key words: (E)-2-styrylquinolin-4(1H)-ones, acridin-9(10H)-ones,
Diels–Alder reactions, N-methylmaleimide, NMR
in moderate to good yields (45–56%, Table 1). These ex-
perimental conditions proved to be a valuable synthetic
method, since in a one-pot synthesis we achieved the
Diels–Alder and oxidation reactions, leading to final
Acridin-9(10H)-ones are a group of naturally occurring
nitrogen heterocyclic compounds found in plants from
Rutaceae family,1 exhibiting significant antifungal, anti-
leishmanial, and antimalaria activities.2 Certain acridin-
9(10H)-one derivatives are also known for their antiviral
activity,3 being recently described as a new class of non-
nucleoside inhibitors of Herpes simplex virus-1 (HSV-1),
antitumoral activity, and DNA intercalating anticancer
drugs.4
products 4a–c. This in situ oxidation of 3a–c led us to
study the oxidation of these compounds with chloranil in
dry 1,4-dioxane at 80 °C. In this way the desired com-
pounds 4a–c were obtained in very good yields (87–90%,
Scheme 1).
Compounds 3a–c are not the expected adducts 2a–c from
the reaction of 1a–c with N-methylmaleimide. Their for-
mation can be explained by the 1,3-hydrogen shift of
structures 2a–c, presumably facilitated by the stabilised
quinolin-4(1H)-ones nucleus (Scheme 1).10
Such important biological applications of acridin-9(10H)-
ones led us to study new and efficient methodologies for
their synthesis. In the present work we report for the first
time a study on the reactivity of (E)-2-styrylquinolin-
4(1H)-ones as dienes in Diels–Alder reactions with the
highly reactive dienophile N-methylmaleimide, leading to
acridin-9(10H)-ones. In this study we used (E)-1-methyl-
2-styrylquinolin-4(1H)-one derivatives5 to avoid conju-
gate Michael additions to N-methylmaleimide.6
R
R
Me
Me
N
Me
N
N
O
O
O
O
NMe
iii
O
O
4a–c
1a–c
The reaction of 1a–c with an excess of N-methylmaleim-
ide (6 mol equiv), in refluxing toluene, gave 3a–c in mod-
erate to good yields (34–52%).7,8 Some starting material
1a–c was recovered (13–15%), and traces of the oxidized
adducts 4a–c were also found (Scheme 1, Table 1). Sev-
eral modifications on the experimental procedure were
made [e.g., increasing the amount of dienophile (9 mol
equiv), changing the volume of solvent (from 3 mL to 1.5
mL) and reaction time (from 72 h to 4 d)] but the final re-
sults were not better. Thus, we decided to increase the re-
action temperature and perform the Diels–Alder reaction
in refluxing 1,2,4-trichlorobenzene for 24 hours, but un-
der these conditions 3a–c were obtained in low yields
Me
N
O
O
i
ii
R
R
Me
Me
N
7
5
N
6a
4
8
9
5a
11b
3a
11
10a
11a
O
O
10
3
H
O
O
NMe
NMe
1
O
O
2a–c
a R = H
3a–c
b R = OMe
c R = Cl
Scheme 1 Reagents and conditions: (i) Diels–Alder reaction under
classical heating conditions and microwave irradiation and using
Lewis acids (Tables 1 and 2); (ii) chloranil, anhyd 1,4-dioxane, 80 °C,
3 h, N2; (iii) 1,2,4-trichlorobenzene, 180 °C, N2 (Tables 1 and 2).
SYNLETT 2012, 23, 889–892
Advanced online publication: 28.02.2012
DOI: 10.1055/s-0031-1290600; Art ID: D71911ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
2

890
A. I. S. Almeida et al.
LETTER
The advantages of microwave irradiation in cycloaddition ried out with 20 mol% of Sc(OTf)3 in 1,2,4-
reactions11 led us to study the Diels–Alder reactions of trichlorobenzene at 180 °C for 24 hours, with traces of 3a
(E)-1-methyl-2-styrylquinolin-4(1H)-ones 1a–c with N- and 7% of the starting material 1a being formed (Table 2,
methylmaleimide under these conditions. However, after entry 5).
several attempted experimental conditions (solvent, tem-
perature, and reaction time) we found that using 1,2,4-
trichlorobenzene as solvent, at 150 °C for one hour, com-
pounds 3a–c were obtained in low yields (13–34%) and
This study was also extended to other (E)-1-methyl-2-
styrylquinolin-4(1H)-ones 1b,c (Table 2). In the case of
1b with 20 mol% of Sc(OTf)3 or AlCl3 in refluxing 1,2,4-
trichlorobenzene, 4b was obtained in poor to moderate
yields (20% and 41%, respectively; Table 2, entries 6 and
7). The best results were also obtained when using
Sc(OTf)3 as catalyst in 1,2,4-trichlorobenzene at 180 °C
for 27 hours, compound 4b obtained in 51% yield
(Table 2, entry 8). On the other hand, adduct 4c was ob-
tained in good yield (50%), by treating 1c with 20 mol%
of Sc(OTf)3 in 1,2,4-trichlorobenzene at reflux for 24
hours (Table 2, entry 9).
The main features of the 1H NMR spectra of cycloadducts
3a–c are: i) the absence of the doublets due to the reso-
nances of the vinylic protons H-a and H-b, the character-
istic of the starting quinolones 1a–c; ii) the presence of
also traces of their oxidised forms 4a–c. Taking the ad-
vantages of microwave irradiation of eliminating hazard-
ous solvents into account,12 we decided to carry out the
cycloaddition reaction in solvent-free conditions and 800
W irradiation power. After irradiating the reaction mix-
ture of 1a and N-methylmaleimide for 1.3 hours, only
compound 3a was obtained (50%). For the other deriva-
tives 2b,c a big degradation was found in the reaction
mixture.
Lewis acids catalysis of Diels–Alder reactions is of con-
siderable interest,13 due to its striking rate acceleration and
high regio- and stereoselectivities in comparison with the
uncatalyzed process.11,14 Thus, we decided to study the
protons in the aliphatic region, where we can distinguish
Diels–Alder reactions of (E)-1-methyl-2-styrylquinolin-
the doublet at d = 5.00–5.06 ppm due the resonance of
4(1H)-ones 1a–c with N-methylmaleimide in the presence
proton H-11b and two double doublets due the resonance
of 20 mol% of Sc(OTf)3 in refluxing toluene. But the ad-
dition of another 20 mol% of catalyst and three mol equiv-
alents of dienophile was necessary to obtain adduct 3a in
low yield (18%); some starting material 1a was recovered
(28%), and traces of 4a were also found (Table 2, entry 1).
The use of Sc(OTf)3 or AlCl3 in refluxing 1,2,4-trichlo-
robenzene for 24 hours led to the oxidized adduct 4a, in
of protons H-5cis at d = 3.00–3.04 ppm and H-5trans at d =
3.20–3.24 ppm (configuration cis and trans16 confirmed
by their coupling constants J = 9.2–10.6 Hz and J = 3.0–
3.6 Hz, respectively).
The stereochemistry of acridone-type compounds 3a–c
was established by the NOE cross peaks observed in their
NOESY spectra, indicating close proximity between H-
low yields (23% and 36%, respectively; Table 2, entries 2
3a, H-11b, H-5cis, and H-4 and also between H-5trans and
and 3). However, when using Sc(OTf)3, 38% of starting
H-2¢,6¢.
material 1a and 9% of their Z-isomer were recovered15
(Table 2, entry 3). The best conditions to obtain com-
pound 4a (42%) were achieved when the reaction was car-
1
The main features in the H NMR spectra that led us to
differentiate compounds 3a–c from 4a–c are the absence
Table 1 Diels–Alder Reactions of (E)-1-Methyl-2-styrylquinolin-4(1H)-ones 1a–c with N-Methylmaleimide under Classical Heating Condi-
tions and Microwave Irradiation
Compd 1, 3, 4
Yield (%) under classical heating conditions
Yield (%) under microwave irradiation
TCB, 150 °C, 1 ha,c
Toluene, 120 °C, 72 h
TCB, reflux, 24 ha
TCB, 180 °Ca,b
3a
4a
1a
3b
4b
1b
3c
4c
1c
52
25
2
–
34
traces
13
50
–
traces
–
–
41
20
3
–
15
traces
15
56
–
traces
–
–
34
13
5
–
13
traces
13
45
–
traces
–
–
a TCB = 1,2,4-trichlorobenzene.
b Reaction times: 3a, 48 h; 3b, 45 h; 3c, 42 h.
c Reaction performed in closed vessels.
Synlett 2012, 23, 889–892
© Thieme Stuttgart · New York

LETTER
New Syntheses of Acridin-9(10H)-ones
891
Table 2 Effect of Lewis Acid Catalysts in Diels–Alder Reactions of (E)-1-Methyl-2-styrylquinolin-4(1H)-ones 1a–c with N-Methylmaleim-
idea
Entry
1
R
H
Catalyst
Time (h)
72
Temp (°C)
reflux
Yield of 1 (%) Yield of 3 (%) Yield of 4 (%)
Sc(OTf)3 (20 mol%)
28
18
traces
+ 20 mol% after 7 h of reaction
2
3b
4
H
AlCl3 (1 equiv)
24
24
24
24
24
24
27
24
27
reflux
reflux
180
–
–
23
H
Sc(OTf)3 (20 mol%)
AlCl3 (1 equiv)
38
82
7
–
36
H
–
traces
42
5
H
Sc(OTf)3 (20 mol%)
Sc(OTf)3 (20 mol%)
AlCl3 (1 equiv)
180
traces
–
6
MeO
MeO
MeO
Cl
reflux
reflux
180
28
–
20
7
–
41
8
Sc(OTf)3 (20 mol%)
Sc(OTf)3
–
traces
–
51
9
reflux
180
–
50
10
Cl
Sc(OTf)3 (20 mol%)
16
traces
36
a Reactions were performed in 1,2,4-trichlorobenzene, except in entry 1 where toluene was used; 3 equiv + 3 equiv of dienophile after 7 h
reaction.
b A yield of 9% of (Z)-1-methyl-2-styrylquinolin-4(1H)-one was found.
Rathbun, R. K.; Levin, J. I.; Hinrichs, D.; Riscoe, M. K. Exp.
Parasitol. 2006, 114, 47. (c) Kelly, J. X.; Similkstein, M. J.;
Cooper, R. A.; Lane, K. D.; Johnson, R. A.; Janowsky, A.;
Dodean, R. A.; Hinrichs, D. J.; Winter, R.; Riscoe, M.
of aliphatic protons and the presence of a singlet at d =
7.58–7.76 ppm due the resonance of proton H-5 in the
spectra of 4a–c.
In conclusion, we describe here two synthetic methods
leading to acridin-9(10H)-ones. The Diels–Alder reac-
tions of (E)-1-methyl-2-styrylquinolin-4(1H)-ones as
dienes with N-methylmaleimide as dienophile in reflux-
ing toluene led to 4-aryl-2,6-dimethyl-4,5,6,11b-tetra-
hydro-1H-pyrrolo[3,4-a]acridine-1,3,11(2H,3aH)-triones,
which, after oxidation, gave the corresponding acridin-
9(10H)-ones. When the Diels–Alder reactions were car-
ried out in 1,2,4-trichlorobenzene at 180 °C an in situ ad-
duct oxidation occurs giving rise to the oxidized adducts
4-aryl-2,6-dimethyl-1H-pyrrolo[3,4-a]acridine-1,3,11(2H,6H)-
triones in a one-pot method. The Diels–Alder reactions
under Lewis acids catalysis led to the oxidized adducts as
main reaction products in shorter reaction times. The ben-
eficial effect of microwave irradiation in all studied trans-
formations was the shortening of reaction times.
Antimicrob. Agents Chemother. 2007, 51, 4133. (d) Kelly,
J. X.; Smilkstein, M. J.; Brun, R.; Wittlin, S.; Cooper, R. A.;
Lane, K. D.; Janowsky, A.; Johnson, R. A.; Dodean, R. A.;
Winter, R.; Hinrichs, D. J.; Riscoe, M. K. Nature (London)
2009, 459, 270.
(3) (a) Tabarrini, O.; Manfroni, G.; Fravolini, A.; Cecchetti, V.;
Sabatini, S.; De Clercq, E.; Rozenski, J.; Canard, B.;
Dutartre, H.; Paeshuyse, J.; Neyts, J. J. Med. Chem. 2006,
49, 2621. (b) Bernardino, A. M. R.; Castro, H. C.;
Frugulhetti, I. C. P. P.; Loureiro, N. I. V.; Azevedo, A. R.;
Pinheiro, L. C. S.; Souza, T. M. L.; Giongo, V.; Passamani,
F. U.; Magalhães, O.; Albuquerque, M. G.; Cabral, L. M.;
Rodrigues, C. R. Bioorg. Med. Chem. 2008, 16, 313.
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Barzi, A.; Sabatini, S.; Miao, H.; Sissi, C. J. Med. Chem.
1999, 42, 2136. (b) Boumendjel, A.; Macalou, S.; Ahmed-
Belkacem, A.; Blanc, M.; Di Pietro, A. Bioorg. Med. Chem.
2007, 15, 2892. (c) Fadeyi, O. O.; Adamson, S. T.; Myles, E.
L.; Okoro, C. O. Bioorg. Med. Chem. Lett. 2008, 18, 4172.
(d) Gao, C.; Jiang, Y.; Tan, C.; Zu, X.; Liu, H.; Cao, D.
Bioorg. Med. Chem. 2008, 16, 8670. (e) Mayur, Y. C.;
Zaheeruddin, ?.; Peters, G. J.; Lemos, C.; Kathmann, L.;
Prasad, V. V. S. R. Arch. Pharm. Life Sci. 2009, 342, 640.
(5) Almeida, A. I. S.; Silva, V. L. M.; Silva, A. M. S.; Pinto,
D. C. G. A.; Cavaleiro, J. A. S. Synlett 2008, 2593.
(6) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.;
Cavaleiro, J. A. S. Synlett 2006, 1369.
Acknowledgment
Thanks are due to the University of Aveiro, to the Portuguese Foun-
dation for Science and Technology (FCT), and FEDER for funding
the Organic Chemistry Research Unit (project PEst-C/QUI/UI0062/
2011) and the Portuguese National NMR Network. Andreia I. S.
Almeida and Vera L. M. Silva also thank FCT for their PhD (SFRH/
BD/40632/2007) and postdoctoral (SFRH/BPD/27098/2006)
grants, respectively.
(7) General Procedure for the Diels–Alder Reaction of (E)-
1-Methyl-2-styrylquinolin-4(1H)-ones 1a–c with N-
Methylmaleimide in Toluene under Classical Heating
Conditions
References and Notes
A mixture of the appropriate (E)-1-methyl-2-styrylquinolin-
4 (1H)-one 1a–c (0.096 mmol) and N-methylmaleimide
(32.0 mg, 0.29 mmol) in toluene (25 mL) was stirred at 120
°C under N2 atmosphere. An extra excess of N-methylmale-
imide (32.0 mg, 0.288 mmol) was added after a reaction time
(1) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
(2) (a) Meepagala, K. M.; Schrader, K. K.; Wedge, D. E.; Duke,
S. O. Phytochemistry 2005, 66, 2689. (b) Winter, R. W.;
Kelly, J. X.; Smilkstein, M. J.; Dodean, R.; Bagby, G. C.;
© Thieme Stuttgart · New York
Synlett 2012, 23, 889–892

892
A. I. S. Almeida et al.
LETTER
of 48 h. After 72 h the reaction mixture was concentrated,
taken in CH2Cl2 and purified by TLC using a 5:1 mixture of
CH2Cl2–acetone as eluent. The adducts 3a–c were obtained
in moderate yields (3a: 18.60 mg, 52%; 3b: 15.80 mg, 41%;
3c: 13.28 mg, 34%) as a yellow solid, and some starting
material was recovered (1a: 3.26 mg, 13%; 1b: 4.20 mg,
15%; 1c: 3.69 mg, 13%). Also, traces of compounds 4a–c
were found.
(6-NCH3), 114.8 (C-7), 118.9 (C-11a), 121.5 (C-5), 122.8
(C-9), 123.5 (C-3a), 125.0 (C-10a), 128.1 (C-3¢,5¢), 128.3
(C-10), 129.1 (C-4¢), 129.3 (C-2¢,6¢), 134.2 (C-8), 134.9 (C-
11b), 136.5 (C-1¢), 142.1 (C-6a), 143.8 (C-4), 146.7 (C-5a),
165.2 and 166.9 (C-1 and C-3), 176.2 (C-11). ESI(+)-MS: m/
z (%) 369 (100) [M + H]+. HRMS-ESI(+): m/z calcd for
C23H17N2O3 [M + H]+: 369.1239; found: 369.1234.
(10) Price, W. A.; Silva, A. M. S.; Cavaleiro, J. A. S.
Heterocycles 1993, 36, 2601.
(11) (a) Wang, Y.; Wu, J. L.; Dai, W. M. Synlett 2009, 2862.
(b) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.;
Elguero, J.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2009,
4468.
(12) (a) Loupy, A. Chimie 2004, 7, 103. (b) Bougrin, K.; Loupy,
A.; Soufiaoui, M. J. Photochem. Photobiol. C 2005, 6, 139.
(c) Ramesh, E.; Raghunathan, R. Tetrahedron Lett. 2008,
49, 1812.
(13) (a) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007.
(b) Pindur, U.; Lutz, G.; Otto, C. Chem. Rev. 1993, 93, 741.
(c) Houk, K.; Strozier, R. W. J. Am. Chem. Soc. 1973, 95,
4094. (d) Alston, P. V.; Ottenbrite, R. M. J. Org. Chem.
1975, 40, 1111.
(8) Physical Data of 2,6-Dimethyl-4-phenyl-4,5,6,11b-
tetrahydro-1H-pyrrolo[3,4-a]acridine-1,3,11(2H,3aH)-
trione (3a)
Mp 283–284 °C. 1H NMR (300.13 MHz, CDCl3): d = 2.76
(3 H, s, 2-NCH3), 3.04 (1 H, dd, J = 16.2, 10.0 Hz, H-5cis),
3.24 (1 H, dd, J = 16.2, 3.6 Hz, H-5trans), 3.41–3.55 (2 H, m,
H-3a, 4-H), 3.79 (3 H, s, 6-NCH3), 5.01 (1 H, d, J = 8.6 Hz,
H-11b), 7.21–7.24 (2 H, m, H-3¢,5¢), 7.30–7.35 (3 H, m, H-
2¢,4¢,6¢), 7.41 (1 H, ddd, J = 7.8, 7.7, 0.7 Hz, H-9), 7.51 (1 H,
d, J = 8.2 Hz, H-7), 7.69 (1 H, ddd, J = 8.2, 7.7, 1.7 Hz, H-
8), 8.56 (1 H, dd, J = 7.8, 1.7 Hz, H-10). 13C NMR (75.47
MHz, CDCl3): d = 24.6 (2-NCH3), 30.2 (C-5), 34.6 (6-
NCH3), 39.1 (C-11b), 41.2 (C-4), 44.4 (C-3a), 112.6 (C-
11a), 115.2 (C-7), 123.7 (C-9), 125.5 (C-10a), 127.4 (C-10),
127.6 (C-4¢), 127.8 (C-3¢,5¢), 128.5 (C-2¢,6¢), 132.4 (C-8),
139.1 (C-1¢), 141.3 (C-6a), 150.2 (C-5a), 175.78, 175.82 and
173.3 (C-1, C-3 and C-11). ESI(+)-MS: m/z (%) = 373 (100)
[M + H]+, 395 (16) [M + Na]+. HRMS (EI): m/z calcd for
C23H20N2O3: 372.1474; found: 372.1472.
(14) (a) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1990. (b)Fringuelli, F.;
Taticchi, A. The Diels–Alder Reaction: Selected Practical
Methods; John Wiley and Sons: New York, 2002.
(15) Physical Data of (Z)-1-Methyl-2-styrylquinolin-4(1H)-
one
(9) Physical Data of 2,6-Dimethyl-4-phenyl-1H-pyrrolo[3,4-
a]acridine-1,3,11(2H,6H)-trione (4a)
1H NMR (300.13 MHz, CDCl3): d = 3.94 (3 H, s, 1-NCH3),
6.93 (1 H, s, H-3), 7.37–7.54 (7 H, m, H-6, H-8, H-3¢,4¢,5¢,
H-a and H-b), 7.71 (1 H, dt, J = 7.8, 1.6 Hz, H-7), 7.98 (2 H,
dd, J = 7.7, 1.6 Hz, H-2¢,6¢), 8.69 (1 H, dd, J = 8.1, 1.6 Hz,
H-5).
Mp 353–354 °C. 1H NMR (300.13 MHz, CDCl3): d = 3.18
(3 H, s, 2-NCH3), 3.95 (3 H, s, 6-NCH3), 7.38 (1 H, dd, J =
7.9, 7.6 Hz, H-9), 7.51–7.54 (3 H, m, H-7, H-3¢,5¢), 7.57–
7.61 (3 H, m, H-2¢,4¢,6¢), 7.76 (1 H, s, H-5), 7.77 (1 H, ddd,
J = 7.8, 7.7, 1.6 Hz, H-8), 8.56 (1 H, dd, J = 7.9, 1.6 Hz, H-
10). 13C NMR (75.47 MHz, CDCl3): d = 24.3 (2-NCH3), 35.4
(16) The configuration cis and trans of H-5 is established by the
position relative to H-4.
Synlett 2012, 23, 889–892
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