Facile, four-component, domino reactions for the regioselective synthesis of tetrahydrobenzo[g]quinolines

Article abstract of DOI:10.1016/j.tetlet.2011.06.102

Facile, four-component domino reactions of 2-hydroxy-1,4-naphthaquinone, aromatic aldehydes, methyl/ethyl acetoacetate and ammonium acetate in ethanol under microwave irradiation at 100 °C afforded tetrahydrobenzo[g]quinoline- 5,10-diones regioselectively

Full text of DOI:10.1016/j.tetlet.2011.06.102

Tetrahedron Letters 52 (2011) 4562–4566
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile, four-component, domino reactions for the regioselective synthesis
of tetrahydrobenzo[g]quinolines
⇑
Balasubramanian Devi Bala, Kamaraj Balamurugan, Subbu Perumal
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Facile, four-component domino reactions of 2-hydroxy-1,4-naphthaquinone, aromatic aldehydes,
methyl/ethyl acetoacetate and ammonium acetate in ethanol under microwave irradiation at 100 °C
afforded tetrahydrobenzo[g]quinoline-5,10-diones regioselectively in good yields. This transformation
Received 19 May 2011
Revised 22 June 2011
Accepted 26 June 2011
Available online 2 July 2011
presumably proceeds via
a,b-unsaturated triketone generation/Michael addition/regioselective annula-
tion via intramolecular condensation domino sequence.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Domino reaction
Ammonium acetate
Methyl/ethyl acetoacetate
2-Hydroxy-1,4-naphthaquinone
Benzo[g]quinoline-5,10-dione
Designing new multicomponent reactions (MCRs) as well as
improving known MCRs constitute a research area of immense
interest in contemporary organic synthesis.1 In contrast to classical
multistep linear synthetic protocols, MCRs enable expedient and
efficient assembly of molecules of structural complexity and diver-
sity in one-pot operations with facile execution, high atom-
economyand selectivity.1b,1c,2,3 These reactions obviatethe isolation
and purification of intermediates and diminish waste generation,
thereby enhancing the greenness of transformations. Consequently,
MCRs have emerged as a powerful tool for delivering molecular li-
braries needed in combinatorial approaches for the assembly and
lead identification of bioactive compounds.4
The benzo[g]quinoline-5,10-dione skeleton is an important
structural motif prevalent in natural products with interesting bio-
logical properties (Fig. 1). For example, cleistopholine isolated from
cleistopholis patens,5 oncodostigma monosperma,6 meiogyne virgata
polyalthia7 and annona cherimolia,8 exhibits antimicrobial activ-
ity9,10 and anticancer activity against several cell lines,11 besides
serving as intermediate in the synthesis of the antifungal agent,
sampangine.12 Phomazarin, isolated from the cultures of phoma ter-
restris Hansen,13 shows in vitro cytotoxic activity.14 Dielsiquinone
and marcanines A-E, isolated from the stem bark of goniothalamus
marcanii craib, also show cytotoxic activity.15 Synthetic methods
for the construction of tetrahydrobenzo[g]quinoline-5,10-dione
derivatives include hetero Diels–Alder reaction,16 annulation17,18
and aza-Diels–Alder cycloaddition-rearrangement sequence.19
These methods suffer from one or more disadvantages such
as requirement of expensive reagents, prolonged reaction time
and low yield or selectivity. Consequently, now we report a con-
vergent four-component domino protocol for the assembly of
tetrahydrobenzo[g]quinoline-5,10-diones from 2-hydroxy-1,4-
naphthaquinone, aromatic aldehydes, methyl/ethyl acetoacetate
and ammonium acetate in ethanol (Scheme 1) in this Letter. This
work stems from our recently embarked research on the synthe-
sis of structurally diverse, novel heterocycles employing tandem/
domino reactions20 and/or their study of anti-tubercular
activity.21
Initially, we investigated the reaction of 2-hydroxy-1,4-
naphthaquinone, 4-chlorobenzaldehyde, ethyl acetoacetate and
ammonium acetate in ethanol at room temperature. This reaction
O
OH
N
O
Me
N
R4
O
O
R3
Bu
OH
R2
O
MeO
CO2H
N
R1
O
OH
O
R5
Cleistopholine
Phomazarin
Dielsiquinone, R1, R2 = H; R3 = Me; R4, R5 = H
Marcanine A, R1, R2 = H; R3 = Me; R4, R5 = H
Marcanine B, R1 = H; R2 = OMe; R3 = Me; R4, R5 = H
Marcanine C, R1 = H; R2 = OMe; R3 = CH2OH; R4, R5 = H
Marcanine D, R1 = H; R2 = OMe; R3 = Me; R4 = OH; R5 = H
Marcanine E, R1 = Me; R2 = OMe; R3 = Me; R4 = H; R5 = OH
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
Figure 1. Structures of naturally occurring benzo[g]quinoline-5,10-diones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.102

B. Devi Bala et al. / Tetrahedron Letters 52 (2011) 4562–4566
4563
EtOH,
ArCHO
O
O
Relux, 4 h or
O
O
O
Ar
O
2
+
Focused microwave,
120W, 100 ºC, 10 min.
R
R
O
O
OH
NH4OAc
O
N
H
3
1
4
Scheme 1. Synthesis of tetrahydrobenzo[g]quinoline-5,10-diones 4.
Table 1
Optimization of reaction conditions for synthesis of 4k
Entry
Solvent
Conditionsa
Catalyst (mol %)
Yield of 4k (%)
b
b
b
b
b
b
b
b
b
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
MeOH
Ethylene glycol
Glycerol
PEG-400
CH3CN
Water
EtOH
rt, 8 h
Thermal, 4 h
—
—
—
—
—
—
—
—
—
0
78
88
60
45
25
Trace
65
Trace
35
MW, 120 W, 10 min
MW, 120 W, 15 min
MW, 120 W, 10 min
MW, 120 W, 20 min
MW, 120 W, 10 min
MW, 130 W, 20 min
MW, 130 W, 15 min
MW, 120 W, 15 min
MW, 120 W, 15 min
MW, 120 W, 10 min
MW, 120 W, 10 min
MW, 120 W, 10 min
MW, 120 W, 25 min
9
10
11
12
13
14
15
p-TsOH (100)
Sulfamic acid (100)
I2 (10)
CAN (10)
YbCl3 (50)
EtOH
EtOH
EtOH
EtOH
30
38
40
42
EtOH
55
L
-Proline (20)
Ammonia and
16
EtOH
Thermal, 8 h
L
-Prolinec
0
a
b
c
All reactions performed at 100 °C in presence of ammonium acetate.
No catalyst other than ammonium acetate was employed.
NH3 and proline were used instead of NH4OAc.
failed to occur and the starting materials remained unreacted (Ta-
ble 1, entry 1). Hence this reaction mixture was subjected to heat-
ing under reflux, whereupon the reaction could be completed in
4 h affording 4k in 78% yield (Table 1, entry 2). In view of the
advantages associated with the use of microwave irradiation in
performing reactions,22,23 the above reaction was investigated un-
der microwave irradiation at 120 W and 100 °C in EtOH. This reac-
tion went to completion in 10 min affording a higher yield of 4k
(88%) (Table 1, entry 3) than the thermal reaction.
With a view to further optimizing the conditions for the reac-
tion under microwave irradiation, the reaction was also investi-
gated in methanol, ethylene glycol, glycerol, PEG-400, CH3CN and
water (Table 1, entries 4–9). All the alternative solvents used in
place of ethanol resulted in lower yields of 4k.
that the reaction in presence of ammonia instead of ammonium
acetate failed to occur.
Based on the above results, all subsequent reactions for the syn-
thesis of 4 were performed under microwave irradiation (120 W,
100 °C for 10 min) in presence of ammonium acetate in EtOH. Under
these optimized conditions, a study on the substrate scope and gen-
erality of the synthetic protocol was investigated by synthesizing a
library of hitherto unreported methyl/ethyl 2-methyl-5,10-
dioxo-4-aryl-1,4,5,10-tetrahydrobenzo[g]quinoline-3-carboxylates
(4) (Scheme 1 and Table 2). Typically, a mixture of 2-hydroxy-1,4-
naphthoquinone (1), aromatic aldehyde (2), methyl/ethyl acetoace-
tate (3) and NH4OAc (1:1:1:2.5 mmol) in a sealed vial was irradiated
Table 2
The reaction under microwave irradiation was further investi-
gated in presence of Bronsted and Lewis acids, viz. p-TsOH, sulfa-
mic acid, I2, CAN, YbCl3 and L-proline (Table 1, entries 10–16).
Synthesis of compounds 4 via thermal and microwave irradiation reactions
Entry
Compd
Ar
R
Yield of 4 (%)a,b
Thermal MW
The data in Table 1 disclose that (i) these acids diminish the yield
and (ii) the reaction in the absence of the above Lewis or Bronsted
acids affords better yields. It is pertinent to note that a large num-
ber of optimized procedures for the Hantzsch reaction24 for the
synthesis of multisubstituted 1,4-dihydropyridines (1,4-DHPs)
employ catalysts such as triphenylphospine,25 molecular iodine,26
Baker’s yeast,27 silica-supported acids,28 ceric ammonium nitrate
(CAN),29 organocatalysts,30 polymers31 and metal triflates.32 How-
ever, some of these methods suffer from limitations such as high
reaction temperature, prolonged reaction time, incomplete conver-
sion of reactants, expensive metal precursors or environmentally
toxic catalysts. In contrast, the present Hantzsch-type reaction fur-
nishes tetrahydrobenzo[g]quinoline-5,10-diones in very high
yields, considering the number of steps involved, under metal-free
conditions in presence of ammonium acetate, a soft Bronsted acid,
which could serve as a reactant as well as a catalyst. The catalytic
role of ammonium acetate in this reaction is evident from the fact
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
C6H5
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
78
79
78
80
79
80
76
77
75
72
78
79
70
79
80
71
83
85
89
88
84
82
82
85
84
80
88
87
84
83
86
80
4-MeC6H4
4-ClC6H4
3-BrC6H4
2-ClC6H4
2,4-Cl2C6H3
1-Naphthyl
C6H5
4-MeC6H4
4-PriC6H4
4-ClC6H4
3-BrC6H4
2-ClC6H4
2,4-Cl2C6H3
4-O2NC6H4
2-Thienyl
9
10
11
12
13
14
15
16
Et
Et
Et
Et
a
Isolated yield after purification by column chromatography.
Thermal and microwave reactions performed for 4 h and 10 min, respectively.
b

4564
B. Devi Bala et al. / Tetrahedron Letters 52 (2011) 4562–4566
Cl
4'
5'
3'
2'
H
O
6'
O
H
H
6
1'
H
H
H
H
H
4a
5a
9a
3
H
4
1
5
O
7
H
H
2
H
10
8
10a
N
9
H
H
H
O
H-2',6': 7.30, d, 2H,
J = 8.4 Hz
H-3',5': 7.20, d,2H,
J = 8.4 Hz
Cl
129.7
128.4
5.34, s, 1H
H-6,9: 8.01-8.05, m, 2H
37.2
126.1, 126.5
O
O
H
4.10 q, 2H, J = 7.2 Hz
H
60.1
H
182.3
179.9
Me
1
O
66.7
Figure 3. ORTEP diagram for 4c.
1.22, t, 3H, J = 7.2 Hz
14.2
H
Me
N
H
2.53, s, 3H
19.5
H
O
7.12
5.34 ppm due to the H-4, which shows a C,H-COSY correlation with
carbon signal at 37.2 ppm, due to C-4 and HMBCs with ester car-
bonyl at 166.7 ppm, C-10a at 143.8 ppm, C-2 at 144.1 ppm and C-5
at 182.3 ppm (Fig. 2). The CH3 hydrogens of the 1,4-dihydropyridine
ring occur as singlet at 2.53 ppm, which shows HMBCs with C-2 at
144.1 ppm and C-3 at 104.5 ppm. The multiplet in the chemical shift
range of 8.01–8.05 ppm is assigned to H-6 and H-9. Another multi-
plet at 7.61–7.73 ppm is assigned to H-7 and H-8. The H-30,50 show
a doublet at 7.20 ppm (J = 8.4 Hz), while the H-20,60 appear as a dou-
blet at 7.30 ppm (J = 8.4 Hz). The NH proton appears as a br s at
7.12 ppm, which shows HMBC with C-3 at 104.5 ppm. An X-ray crys-
tallographic study of a single crystal of 4c34 (Fig. 3) confirmed the
structure deduced from NMR spectroscopic studies. A plausible
mechanism for the formation of tetrahydrobenzo[g]quinolines (4)
H-7,8: 7.61-7.73, m, 2H
132.8, 134.8
br s, 1H
Figure 2. Selected HMBCs, 1H- and 13C- chemical shifts of 4k.
in a focused microwave oven at 100 °C and 120 W for 10 min.33 After
completion of the reaction (TLC), the products 4 were isolated and
purified by flash column chromatography. All the thermal reactions
went to completion within 4 h. The data in Table 2 indicate that the
reaction under microwave irradiation could be performed in higher
yields conveniently in minutes than the thermal reaction.
The structure of 4 was assigned using one- and two-dimensional
NMR spectroscopic data. The 1H NMR spectrum of 4k has a singlet at
O
H
H
R
NH4OAc
O
NH2
O
AcO
Ar
Ar
2
5
O
3
O
Ar
O
NH3
AcOH
NH2
5
-NH3
O
O
O
O
Ar
O
R
O
7
O
:
H2N
OH
O
Ar
2
6
O
9
OH
1
-H2O
O
O
8
O
O
O
O
O
Ar
R
R
O
Ar
R
H
HN
O
O
O
1
O
Ar
3
O
+
H2N
O
O
H2N
O
11
10
4'
O
Ar
O
O
O
Ar
O
R
R
O
O
-H2O
N
N
H
H
O
OH
12
4
Scheme 2. Probable domino sequence leading to 4.

B. Devi Bala et al. / Tetrahedron Letters 52 (2011) 4562–4566
4565
14. Boger, D. L.; Hong, J.; Hikota, M.; Ishida, M. J. Am. Chem. Soc. 1999, 121, 2471–
2477.
15. Soonthornchareonnon, N.; Suwanborirux, K.; Bavovada, R.; Patarapanich, C.;
Cassady, J. M. J. Nat. Prod. 1999, 62, 1390–1394.
16. (a) Chigr, M.; Fillion, H.; Rougny, A. Terahedron Lett. 1988, 29, 5913–5916; (b)
Echavarren, A. M. J. Org. Chem. 1990, 55, 4255–4260; (c) Nebois, P.; Barret, R.;
Fillion, H. Tetrahedron Lett. 1990, 31, 2569–2572; (d) Nicolaides, D. N.; Awad, R.
W.; Papageorgiou, G. K.; Stephanidou-Stephanatou, J. J. Org. Chem. 1994, 59,
1083–1086.
17. (a) Krapcho, A. P.; Gallagher, C. E.; Mammach, A.; Ellis, M.; Menta, E.; Oliva, A. J.
Heterocycl. Chem. 1997, 34, 27–32; (b) Meghani, P.; Mills, O. S.; Joule, J. A.
Heterocycles 1990, 30, 1121–1129.
is depicted in Scheme 2. Presumably, the intermediate, 3-[1-aryl-
methylidene]-1,2,3,4-tetrahydro-1,2,4-naphthalenetriones (9),
could arise via (i) the Mannich reaction of 2-hydroxy-1,4-naphtho-
quinone (1) with an iminium ion 5 generated from 2 and ammonium
acetate, followed by elimination of ammonia, or (ii) the ammonium
acetate-catalyzed reaction of 1 with aldehyde to afford aldol 8,
which could undergo dehydration. Michael addition of enamine 6,
generated from the reaction of b-ketoester with ammonia, available
from the dissociation of ammonium acetate, to 9, followed by regio-
selective intramolecular condensation affords solely 4 (Scheme 2).
The regioisomer 40 is not formed even in traces in this reaction. This
is presumably due to the higher electrophilicity of the carbonyl at
non-conjugating 3-position in intermediate 11 than the carbonyl
at conjugating 1-position.
In conclusion, we have described an expedient and convergent
four-component domino protocol for the regioselective synthesis
of a library of tetrahydrobenzo[g]quinolines in excellent yields
from readily available simple starting materials. The quinolinedi-
ones obtained in this study could also serve as valuable synthons
for further elaboration into more complex heterocycles of biologi-
cal relevance.
18. Berghot, M. A. Chem. Pap. 2002, 56, 202–207.
19. Cuerva, J. M.; Cárdenas, D. J.; Echavarren, A. M. Chem. Comm. 1999, 17, 1721–
1722.
20. (a) Prasanna, P.; Balamurugan, K.; Perumal, S.; Menéndez, J. C. Green Chem.,
doi:10.1039/c0gc00952k; (b) Balamurugan, K.; Jeyachandran, V.; Perumal, S.;
Menéndez, J. C. Tetrahedron 2011, 67, 1432–1437; (c) Suresh Kumar, R.; Osman,
H.; Perumal, S.; Menéndez, J. C.; Ashraf Ali, M.; Ismail, R.; Soo Choon, T.
Tetrahedron 2011, 67, 3132–3139; (d) Balamurugan, K.; Perumal, S.; Menéndez,
J. C. Tetrahedron 2011, 67, 3201–3208; (e) Indumathi, S.; Perumal, S.;
Menéndez, J. C. J. Org. Chem. 2010, 75, 472–475; (f) Balamurugan, K.;
Perumal, S.; Kumar Reddy, A. S.; Yogeeswari, P.; Sriram, D. Tetrahedron Lett.
2009, 50, 6191–6195; (g) Indumathi, S.; Ranjith Kumar, R.; Perumal, S.
Tetrahedron 2007, 63, 1411–1416; (h) Srinivasan, M.; Perumal, S. Tetrahedron
2007, 63, 2865–2874; (i) Karthikeyan, S. V.; Perumal, S. Tetrahedron Lett. 2007,
48, 2261–2265.
21. (a) Ranjith Kumar, R.; Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. J.
Med. Chem. 2008, 51, 5731–5735; (b) Ranjith Kumar, R.; Perumal, S.;
Senthilkumar, P.; Yogeeswari, P.; Sriram, D. Tetrahedron 2008, 64, 2962–
2971; (c) Balamurugan, K.; Jeyachandran, V.; Perumal, S.; Manjashetty, T. H.;
Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2010, 45, 682–688; (d)
Karthikeyan, S. V.; Perumal, S.; Krithika, A. S.; Yogeeswari, P.; Sriram, D.
Bioorg. Med. Chem. Lett. 2009, 19, 3006–3009; (e) Ranjith Kumar, R.; Perumal,
S.; Manju, S. C.; Bhatt, P.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett.
2009, 19, 3461–3465; (f) Ranjith Kumar, R.; Perumal, S.; Senthilkumar, P.;
Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2009, 44, 3821–3829.
22. (a)For general selected reviews and monographs of microwave-assisted
organic synthesis, see: Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH, 2002; (b) Varma, R. S. Advances in Green Chemistry: Chemical Synthesis
Using Microwave Irradiation; AstraZeneca Research Foundation India, 2002; (c)
Tierney, J.; Lindstrom, P. Microwave Assisted Organic Synthesis; Blackwell, 2004;
(d) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250–6284.
Acknowledgments
S.P. thanks (i) the Council of Scientific and Industrial Research,
New Delhi for a major research project (01(2433)/10 EMR-II) and
(ii) Department of Science and Technology, New Delhi for funds
under IRHPA program for the purchase of a high resolution NMR
spectrometer. B.D.B. thanks the University Grants Commission,
New Delhi for the award of a Junior Research Fellowship. K.B.
thanks the Council of Scientific and Industrial Research, New Delhi
for the award of a Senior Research Fellowship.
23. For a review of the impact of microwaves in green chemistry, see: Strauss, C. R.;
Varma, R. S. Top. Curr. Chem. 2006, 266, 199–231.
Supplementary data
24. Hantzsch, A. Chem. Ber. 1881, 14, 1637–1638.
25. Debache, A.; Ghalem, W.; Boulcina, R.; Belfaitah, A.; Rhouati, S.; Carboni, B.
Tetrahedron Lett. 2009, 50, 5248–5250.
26. Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C. F. Tetrahedron Lett. 2005, 46, 5771–5774.
27. Kumar, A.; Maurya, R. A. Tetrahedron Lett. 2007, 48, 3887–3890.
28. Mobinikhaledi, A.; Foroughifar, N.; Fard, M. A. B.; Moghanian, H.; Ebrahimi, S.;
Kalhor, M. Synth. Commun. 2009, 39, 1166–1174.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.102.
References and notes
29. Ko, S. K.; Yao, C. F. Tetrahedron 2006, 62, 7293–7299.
1. (a) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168–3210; (b) Zhu, J.;
Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005; (c)
Domling, A. Chem. Rev. 2006, 106, 17–89.
2. (a) Ugi, I. Pure Appl. Chem. 2001, 73, 187–191; (b) Nagawade, R. R.; Shinde, D. B.
Acta Chim. Slov. 2007, 54, 642–646; (c) D’Souza, D. M.; Mueller, T. J. Chem. Soc.
Rev. 2007, 36, 3169–3173; (d) Cariou, C. C. A.; Clarkson, G. J.; Shipman, M. J. Org.
Chem. 2008, 73, 9762–9764.
3. (a) Bannwarth, W.; Felder, E. Combinatorial Chemistry; Wiley-VCH: Weinheim,
2000; (b) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101–
4111; (c) Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471–1499; (d) Bienayme,
H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321–3329; (e)
Vasuki, G.; Kumaravel, K. Tetrahedron Lett. 2008, 49, 5636–5638.
4. For recent reviews, see: (a) Ugi, I.; Domling, A.; Werner, B. Heterocycl. Chem.
2000, 37, 647–658; (b) Ugi, I.; Heck, S. Comb. Chem. High Throughput Screening
2001, 4, 1–34; (c) Zhu, J. Eur. J. Org. Chem. 2003, 1133–1144; (d) Hulme, C.;
Gore, V. Curr. Med. Chem. 2003, 10, 51–80; (e) Orru, R. V. A.; De Greef, M.
Synthesis 2003, 1471–1499; (f) Weber, L. Curr. Med. Chem. 2002, 9, 2085–2093.
5. Waterman, P. G.; Muhammad, I. Phytochemistry 1985, 24, 523–527.
6. Bou-Abdullah, E.; Jossang, A.; Tadic, D.; Leboeuf, M.; Cave, A. J. Nat. Prod. 1989,
52, 273–278.
30. (a) Evans, C. G.; Gestwicki, J. E. Org. Lett. 2009, 11, 2957–2959; (b) Karade, N. N.;
Budhewar, V. H.; Shinde, S. V.; Jadhav, W. N. Lett. Org. Chem. 2007, 4, 16–19; (c)
Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946–1952.
31. (a) Breitenbucher, J. G.; Figliozzi, G. Tetrahedron Lett. 2000, 41, 4311–4315; (b)
Dondoni, A.; Massi, A.; Minghini, E.; Bertolasi, V. Tetrahedron 2004, 60, 2311–
2326.
32. (a) Kikuchi, S.; Iwai, M.; Murayama, H.; Fukuzawa, S. I. Tetrahedron Lett. 2008,
49, 114–116; (b) Donelson, J. L.; Gibbs, R. A.; De, S. K. J. Mol. Catal. Chem. 2006,
256, 309–311; (c) Wang, L. M.; Sheng, J.; Zhang, L.; Han, J. W.; Fan, Z. Y.; Tian,
H.; Qian, C. T. Tetrahedron 2005, 61, 1539–1543.
33. General procedure for synthesis of 4: Microwave irradiation method: A vial
containing a mixture of 2-hydroxy-1,4-naphthoquinone (1) (1 mmol), aromatic
aldehyde (1 mmol), methyl/ethyl acetoacetate (3) (1 mmol), and NH4OAc
(2.5 mmol) in ethanol (5 ml) was sealed and placed in
a CEM Discover
microwave oven. The vial was subjected to microwave irradiation, programed
at 100 °C and 120 W. After a period of 3–5 min, the temperature reached a
plateau, 100 °C, and remained constant. After completion of the reaction
(10 min), the vial was cooled to room temperature and poured in to water
(50 ml). The precipitated solid was filtered and and purified by column
chromatography using a 7:1 petroleum ether-AcOEt mixture, to yield pure 4.
Conventional heating method: A mixture of 2-hydroxy-1,4-naphthoquinone 1
(1 mmol), the suitable aromatic aldehyde (1 mmol), methyl/ethyl acetoacetate
3 (1 mmol), and NH4OAc (2.5 mmol) in ethanol (12 ml) was heated to reflux in
an oil bath for 4 h. After completion of the reaction (TLC), the reaction mass
was poured into water (50 ml). The precipitated solid was filtered and purified
by the column chromatography using a 7:1 petroleum ether-AcOEt mixture, to
yield pure 4.
7. Tadic, D.; Cassels, B. K.; Leboeuf, M.; Cave, A. Phytochemistry 1987, 26, 537–541.
8. Rios, J. L.; Cortes, D.; Valverde, S. Planta Med. 1989, 55, 321–323.
9. Koyama, J.; Tagahara, K.; Konoshima, T.; Kozuka, M.; Yano, Y.; Taniguchi, M.
Chem. Exp. 1990, 5, 557–560.
10. Bracher, F. Arch. Pharm. (Weinheim) 1994, 327–371.
11. Lee, H.; Hong, S.-S.; Choi, J.-Y.; Cho, J.; Kim, Y.-H. Arch. Pharm. Res. 1998, 21, 73–75.
12. (a) Bracher, F. Liebigs Ann. Chem. 1989, 87–88; (b) Peterson, J. R.; Zjawiony, J. K.;
Liu, S.; Hufford, C. D.; Clark, A. M.; Rogers, R. D. J. Med. Chem. 1992, 35, 4069–
4077; (c) Zjawiony, J. K.; Srivastava, A. R.; Hufford, C. D.; Clark, A. M.
Heterocycles 1994, 39, 779–800.
13. (a) Kogl, F.; Sparenburg, J. Recl. Trav. Chim. Pays-Bas 1940, 59, 1180; (b) Kogl, F.;
Quackenbush, F. W. Recl. Trav. Chim. Pays-Bas 1944, 63, 251–260; (c) Kogl, F.;
van Wessem, G. C.; Elsbach, O. I. Recl. Trav. Chim. Pays-Bas 1945, 64, 23–29.
Characterization data of compound 4k are given below.
Ethyl 4-(4-chlorophenyl)-2-methyl-5,10-dioxo-1,4,5,10-tetrahydrobenzo[g]
quinoline-3-carboxylate (4k): Isolated as red brown solid. Yield: 88%;
mp = 209 °C; 1H NMR (300 MHz, CDCl3) dH: 1.22 (t, 3H, J = 7.2 Hz), 2.53 (s,
3H), 4.10 (q, 2H, J = 7.2 Hz), 5.34 (s, 1H), 7.12 (br s, 1H), 7.20 (d, 2H, J = 8.4 Hz),
7.30 (d, 2H, J = 8.4 Hz), 7.61–7.73 (m, 2H), 8.01–8.05 (m, 2H). 13C NMR (75 MHz,

4566
B. Devi Bala et al. / Tetrahedron Letters 52 (2011) 4562–4566
CDCl3) dC: 14.2, 19.5, 37.2, 60.1, 104.5, 118.7, 126.1, 126.5, 128.4, 129.7, 130.1,
132.5, 132.8, 134.8, 136.8, 143.8, 144.1, 166.7, 179.9, 182.3. Anal. Calcd for
23H18ClNO4: C, 67.73; H, 4.45; N, 3.43%. Found C, 67.81; H, 4.36; N, 3.49%.
Crystallographic Data Centre as supplementary publication number CCDC
823746. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223-336033 or
e-mail:deposit@ccdc.cam.ac.uk].
C
34. Crystallographic data (excluding structure factors) for tetrahydrobenzo[g]
quinoline-5,10-dione 4c in this Letter have been deposited with the Cambridge