Synthesis of annelated [a]aza-anthracenones and thieno[3,2-g]aza- naphthalenones through ring transformation of 2H-pyran-2-one followed by photocyclization

Article abstract of DOI:10.1016/j.tet.2005.02.012

A concise synthesis of some new classes of heterocycles (4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a-diaza-cyclopenta[a]anthracen-6- carbonitriles and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-diazabenzo[a] anthracene-7-carbonitriles) has been developed by the

Full text of DOI:10.1016/j.tet.2005.02.012

Tetrahedron 61 (2005) 3781–3787
Synthesis of annelated [a]aza-anthracenones and
thieno[3,2-g]aza-naphthalenones through ring transformation of
2H-pyran-2-one followed by photocyclization*
Ashoke Sharon,a Ramendra Pratap,b Prakas R. Maulika and Vishnu Ji Ramb,
*
aDivision of Molecular and Structural Biology, Central Drug Research Institute, Lucknow 226001, India
bMedicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
Received 18 August 2004; revised 21 January 2005; accepted 3 February 2005
Abstract—A concise synthesis of some new classes of heterocycles (4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a-diaza-cyclopenta[a]anthracen-
6-carbonitriles and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-diazabenzo[a]anthracene-7-carbonitriles) has been developed by the ring
transformation of suitably functionalized 2H-pyran-2-one with a-oxoketene cyclic aminals to intermediates (8-aroyl-5-aryl-2,3-dihydro-1H-
imidazo[1,2-a]pyridine-7-ylidene)-acetonitriles and (9-aroyl-6-aryl-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-8-ylidene)-acetonitriles)
followed by their photocyclization either in CHCl3 or acetonitrile. This reaction was further explored for the synthesis of methyl 4-aryl-
11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carboxylate, 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclo-
penta[a]anthracene-6-carbonitriles, 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a,10-triazabenzo[a]anthracene-7-carbonitriles, 4-aryl-10-oxo-
1,2,3,10-tetrahydro-9-thia-1,3a-diazadicyclopenta[a,g]naphthalene-6-carbonitriles and 5-aryl-11-oxo-1,3,4,11-tetrahydro-2H-10-thia-1,4a-
diazacyclopenta[b]phenanthrene-7-carbonitriles from the similar reactions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
reported in the literature.
Protein tyrosine kinases including Src1 are key elements that
regulate numerous cell functions such as cell growth and
differentiation through signal transduction. Over activation
and expression of Src is responsible for various diseases
including cancer.2 4-Anilino-1-azaanthracene-3-carbo-
nitrile and aza analogs of quinoline have been found highly
effective as Src kinase inhibitors in the treatment of cancer
and other diseases.3 Various compounds with anthracene (I)
and azaanthracene (II) basic skeletons have been used in the
clinical management of leukemia, breast and ovarian
cancer.4 The development of resistance against clinically
used anticancer drugs, necessitated the design and synthesis
of a new class of heterocycles, which could not only
improve the therapeutic efficacy against multiple drug
resistance but were also less toxic.5 The therapeutic
significance of 9,10-anthraquinone highlightened our inter-
est in the synthesis of annelated [a]aza-anthracenone (III),
and thieno[3,2-g]aza-naphthalenone (IV) not previously
Non-annelated azaanthraquinones have been synthesized
either by Diels–Alder reaction of azanaphthoquinone with
an appropriate diene,6 classical Friedel–Crafts7 reactions or
oxidation of 9,10-dihydroazaanthracene.8 Considering
the electronic aspects of prototype structures I and II,
annelated [a] azaanthracenone (III) and thieno [3,2-g]
* CDRI communication no: 6649.
Keywords: Azaanthracenones; Thieno[3,2-g]azanaphthalenone; Ring trans-
formation; Photocyclization.
*
Corresponding author. Tel.: C91 522 2262411; fax: C91 522 2623405;
e-mail: vjiram@yahoo.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.012

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A. Sharon et al. / Tetrahedron 61 (2005) 3781–3787
aza-naphthalenone (IV) were designed and by replacing the
carbonyl oxygen with an electron withdrawing cyano
substituent to retain an almost similar electronic status of
the molecules.
UV spectrum of 5 in DMSO. The initial absorption band at
435 nm disappeared after irradiation for 2 h with a
hypsochromic shift and the appearance of a new absorption
maxima at 385 nm (Fig. 1, Scheme 2).
The ubiquitous presence of 2H-pyran-2-one (4) in various
natural products and its unique electronic topography led us
to consider its suitability for ring transformation reactions to
generate molecular diversity.9 Herein, we report a concise
and efficient synthesis of anneleted [a]aza-anthracenones
(6), triaza-cyclopenta[a]anthracenones (8) and thieno[3,2-
g]aza-naphthalenones (9) through ring transformation
reaction of suitably functionalized 2H-pyran-2-one 4 with
a-oxoketene cyclic aminals 3a–h followed by
photocyclization.
Figure 1. Absorption maxima of intermediate 5a (435 nm) and product 6a
(385 nm) after irradiation (200 W electric bulb) for 2 h.
2. Results and discussion
To generate molecular diversity, a reaction of 4 with
different a-oxoketene cyclic aminals (3e,h) derived from
3,3-bis-methylsulfanyl-1-pyridin-3-yl-propanone was
carried out analogously to obtain 8 as the major product
(Scheme 3).
Our strategy to synthesize 4-aryl-11-oxo-1,2,3,11-tetra-
hydro-1,3a-diazacyclopenta[a]anthracene-6-carbonitriles
(6a–e) and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-
diazabenzo[a]anthracene-7-carbonitriles (6f,g) was based
on the ring transformation of 2H-pyran-2-ones10 (4) with
a-oxoketene cyclic aminals11 (3), obtained from the
reaction of a-oxoketene dithioacetal (1) with 1,2 or 1,3-
diaminoalkanes (2) in alcohol at reflux temperature
(Scheme 1).
The ring transformation and photocyclization reactions
were also achieved in a single step by simply irradiating a
solution of a mixture of 3 and 4 in the presence of NaH in
THF for 10–15 h.
In this reaction, there are two possible modes of photo-
cyclization of the intermediate involving positions 2 and 4
of the pyridine ring and the a-vinylic carbon adjacent to the
nitrile functionality. Isolation of only one product from this
reaction, indicated the involvment of either C2 or C4 of the
pyridine ring in the photocyclization. The proton NMR of 8f
showed one singlet for the C2 proton at d 9.54 and
confirmed the cyclization involving C4 of the pyridine ring.
The downfield shift of the C2 proton was probably due to
strong intramolecular H-bonding with the neighboring
carbonyl oxygen. The two doublets for the C5 and C6
protons at d 7.58 and 8.57, respectively, with 5.7 Hz
coupling constant further supported cyclization involving
C4. The scope of the reaction was further explored by
synthesizing thieno[3,2-g]azanaphthalenones (9) directly by
irradiating a solution of 2H-pyran-2-one (4) and
a-oxoketene cyclic aminals 3 in the presence of NaH in
THF for 15 h in moderate yield and produced a new class of
heterocycle (Scheme 4).
Scheme 1. Preparation of a-oxoketene cyclic aminals (3).
Thus, stirring an equimolar mixture of 3 and 4 in the
presence of powdered KOH in dry DMF for 24 h at ambient
temperature in normal light provided 6 directly in poor yield
(8%) after usual workup. Thus, attempts were made to trap
the intermediate to understand the course of the reaction as
well as to improve the yield of the final product.
The nature of the substitutents present at positions 3 and 4 of
the pyran ring greatly influence the ring transformation
reactions. An electron withdrawing substituent, especially at
position 3, is an essential requirement to enhance the
electrophilicity of C6 of the pyran ring which facilitates the
nucleophile induced ring transformation reactions. 2H-
Pyran-2-ones (4) can be considered as a cyclic ketene
hemithioacetal, prone to nucleophilic attack at C6 due to
extended conjugation. a-Oxoketene cyclic aminals (3) are
endowed with three nucleophilic centers, two of them due to
the presence of two secondary amino groups and other due
to the vinylic carbon, adjacent to the cyano function.
The intermediate 5 was synthesized from the usual ring
transformation of 2H-pyran-2-one (4) by 3 in the dark and
purified by Si-gel column chromatography to isolate 5 as a
pure product. The structure of intermediate (5) was
confirmed by 1H NMR spectroscopy and mass
spectrometry. A solution of intermediate (5) was photo-
chemically cyclized to 6 in 50% yield by irradiating its
solution in chloroform with a 200 W electric bulb. The
progress of the reaction was also monitored by recording the

A. Sharon et al. / Tetrahedron 61 (2005) 3781–3787
3783
Scheme 3. Preparation of triaza-cyclopenta[a]anthracene-6-carbonitriles 8.
5.The structure was further confirmed by spectroscopy and
also by single crystal X-ray diffraction analysis of 6f
(Fig. 2).12 The presence of chloroform in the asymmetric
unit of the crystal structure may be due to the presence of
strong intermolecular H-bond between hydrogen atom of
chloroform and N20 of the cyano group [C28–H28/N20A:
˚
˚
H/AZ2.36 A, D/AZ3.15(2) A and :(DHA)Z136.88].
The possibility of a free radical mechanism for photo-
cyclized product 6 was ruled out on the basis of formation of
the same product in the presence of TEMPO. Thus, the
reaction possibly proceeds through a photochemically
allowed conrotatory cyclization13 followed by aerial
oxidation of dihydro intermediate to yield 6.A plausible
mechanism of this reaction is depicted in Scheme 2, where
the nitrogen nucleophile attacks at C6 of the pyran ring with
ring opening followed by decarboxylation and recyclization
involving the vinylic carbon and C4 of the pyran ring with
elimination of methyl mercaptan to yield 5 (Scheme 2,
Fig. 3).
The stereoselectivity in the formation of intermediate 5 has
possibly arised from strong intramolecular hydrogen bond-
ing between the NH and CO functionalities or steric
hindrance which plays a crucial role in restricting the
Scheme 2. Proposed mechanism for the formation of aza-anthracenones.
Thus, the possibility for the formation of two products
existed depending upon the initial involvement of either of
the two secondary amino groups or vinylic carbon of the
ring transformed product. The progress of the reaction
through intermediate 7 (Scheme 2) was ruled out on the
basis of the structure of the photochemically cyclized
product 6 which can only be obtained from intermediate
Scheme 4. Preparation of thieno[3,2-g]azanaphthalenones (10).

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A. Sharon et al. / Tetrahedron 61 (2005) 3781–3787
In summary, our methodology provides a concerted
approach to the synthesis of fused heterocyclic systems,
using readily available starting materials under mild
conditions. It opens as an efficient diversity-orientated
synthetic route for the synthesis of complex nitrogen
bridgehead aza-heterocycles.
3. Experimental
3.1. General
All reactions were conducted in flame dried glassware under
nitrogen atmosphere. Pre-coated Merck TLC plates were
used for monitoring reactions. Column chromatographic
separations were performed on silica gel (60–120 mesh). IR
spectra were taken on a Shimadzu 8201 PC FTIR
Spectrophotometers. 1H and 13C NMR spectra were
recorded, on Bruker DRX 300 or DPX 200 spectrometers.
13C NMR assignments were obtained from DEPT and
inverse H–C one bond and multiple bond correlation
experiments. Mass spectra were recorded on JEOL SX-
102 (FAB) spectrometers. Combustion analyses were
performed on Elementar Vario EL III Carlo Erba 1108
analyzers.
Figure 2. ORTEP diagram of 6f showing the X-ray molecular structure in
50% probability level, solvent of crystallization ‘chloroform’ has been
shown in the crystal structure.
3.2. General procedure for the synthesis of imidazo[1,2-a]-
pyridines (5a–e) and pyrido[1,2-a]pyrimidine (5f,g)
A mixture of 2H-pyran-2-ones 4 (1 mmol), a-oxoketene
cyclic aminal 3 (1 mmol) and NaH (60% suspension,
2.5 mmol) in dry THF (20 mL) was stirred for 2 h at
5–10 8C. After additional stirring for another 10 h at
20–25 8C, the reaction mixture was poured into ice-water
(50 mL) and neutralized with 10% HCl. The separated solid
was filtered, washed with water (50 mL) and dried. The
entire reaction was carried out in the dark to prevent
photocyclization. The crude solid obtained was further
purified by column chromatography using 50% hexane–
CHCl3 as eluent in the dark.
Figure 3. Chemical structure of 5b showing HMBC and NOE.
rotation of the aroyl group, to attain E-geometry. The
intermediates 5 isolated from the reaction were character-
ized by IR and NMR spectroscopy and mass spectrometry as
(E)-2-(8-aroyl-5-aryl-2,3-dihydro-1H-imidazo[1,2-a]pyri-
dine-7-ylidene)acetonitrile (5, nZ1) and pyrido[1,2-a]-
pyrimidin-8-ylidene)acetonitrile (5, nZ2). The proton
NMR spectrum of 5b showed two CH proton singlets at
6.33 and 3.59 ppm, a methyl singlet at 3.83 ppm and a set of
aliphatic methylene protons as multiplet centered at
3.86 ppm, two sets of ortho coupled doublets at 7.34 and
7.57 and a broad singlet at 8.49 ppm for the NH proton. The
13C NMR spectrum provided two methylene carbons at 42.7
and 46.9 ppm, one methyl carbon at 55.4 ppm, two
methylene carbons at 72.9 and 110.7 ppm as shown in
Figure 3. Three aromatic methyne carbons at 114.3, 129.0
and 129.6 ppm and the presence of two carbons at
129.6 ppm was corroborated in the HSQC experiment.
Moreover, the 13C assignments were carried out by the
combined use of NOE difference, HSQC and HMBC
experiments. The high field shift of the olefinic CH in the
1H NMR spectrum at 3.59 ppm and at 72.7 ppm in the 13C
NMR was attributed to the shielding effect of the carbonyl
and nitrile functionalities of 5b.
3.2.1. [8-(4-Chlorobenzoyl)-5-phenyl-2,3-dihydro-1H-
imidazo[1,2-a]pyridin-7-ylidene]-acetonitrile
(5a).
Yields 52%; brown-red solid; mp 185–190 8C dec.; IR
(neat): nmaxZ3352, 2923, 2855, 2168, 1638, 1595, 1517,
1
1287, 1085, 1010 cmK1; H NMR (200 MHz, DMSO): d
3.53 (s, 1H, CH), 3.62–3.67 (m, 2H, NCH2), 3.83–3.87 (m,
2H, NCH2), 6.01 (s, 1H, CH), 7.49–7.62 (m, 9H, ArH), 8.40
(bs, 1H, NH); FAB (MS) 374 (MCC1); C22H16ClN3O2
(373.10) calcd: C, 70.68; H, 4.31; N, 11.24; found: C, 70.51;
H, 4.41; N, 11.39.
3.2.2. [8-(4-Chlorobenzoyl)-5-(4-methoxyphenyl)-2,3-
dihydro-1H-imidazo[1,2-a]pyridin-7-ylidene]-aceto-
nitrile (5b). Yields 62%; brown-red solid; mp 175–180 8C
dec.; IR (neat) nmax 3353, 3019, 2927, 2856, 2175, 1640,
1597, 1529, 1295, 1216, 1091, 1013 cmK1 1H NMR
;
(300 MHz, CDCl3) d 3.58 (s, 1H, CH), 3.83–3.89 (m, 7H,
OCH3 and 2NCH2), 6.32 (s, 1H, CH), 6.96 (d, JZ8.7 Hz,
2H, ArH), 7.32–7.39 (m, 4H, ArH), 7.57 (d, JZ8.7 Hz, 2H,
ArH), 8.49 (bs, 1H, NH); 13C NMR (75 MHz in ppm) d
42.7, 46.9, 55.4, 72.9, 110.7, 114.3, 122.1, 125.4, 129.6,
138.5, 149.7, 156.8, 160.7, 192.8; FAB (MS) 404 (MCC1);

A. Sharon et al. / Tetrahedron 61 (2005) 3781–3787
3785
C23H18ClN3O (403.11) calcd: C, 68.40; H, 4.49; N, 10.40;
found: C, 68.61; H, 4.38; N, 10.59.
chromatography using 1% methanol in chloroform as
eluent.
3.3.1. 8-Chloro-11-oxo-4-phenyl-1,2,3,11-tetrahydro-
1,3a-diaza-cyclopenta[a]anthracene-6-carbonitrile (6a).
Yields 39%; yellow powder; mp O250 8C; IR (KBr) nmax
3.2.3. [8-(4-Chlorobenzoyl)-5-(4-fluorophenyl)-2,3-di-
hydro-1H-imidazo[1,2-a]pyridin-7-ylidene]-acetonitrile
(5c). Yields 60%; brown-red solid; mp 165–170 8C dec.; IR
(neat) nmax 3367, 3019, 2926, 2177, 1641, 1596, 1527, 1292,
3434, 2925, 2859, 2174, 1598, 1515 cmK1 1H NMR
;
1
1216, 1091, 1011 cmK1; H NMR (200 MHz, CDCl3): d
(200 MHz, DMSO) d 3.84–3.87 (m, 2H, NCH2), 4.07–
4.10 (m, 2H, NCH2), 6.41 (s, 1H, CH), 7.21–7.59 (m, 7H,
ArH), 8.17 (d, JZ8.0 Hz, 1H, ArH), 10.00 (bs, 1H, NH);
FAB (MS) 372 (MCC1); C22H14ClN3O (371.08) calcd: C,
71.07; H, 3.80; N, 11.30; found: C 71.16; H, 3.71; N, 11.39.
3.62 (s, 1H, CH), 3.84 (m, 4H, 2NCH2), 6.33 (s, 1H, CH),
7.11–7.72 (m, 8H, ArH), 8.51 (bs, 1H, NH); FAB (MS) 453
(MCC1); C22H15ClFN3O (391.01) calcd: C, 67.44; H, 3.86;
N, 10.72; found: C, 67.61; H, 3.78; N, 10.69.
3.3.2. 8-Chloro-4-(4-methoxyphenyl)-11-oxo-1,2,3,11-
tetrahydro-1,3a-diaza-cyclopenta[a]anthracene-6-
carbonitrile (6b). Yields 51%; yellow powder; mp
O250 8C; IR (KBr) nmax 3447, 3255, 2910, 2194, 1646,
3.2.4. [8-(4-Chlorobenzoyl)-5-naphthalen-1-yl-2,3-di-
hydro-1H-imidazo[1,2-a]pyridin-7-ylidene]-acetonitrile
(5d). Yields 62%; brown-red solid; mp 135–139 8C dec.; IR
(neat) nmax 3431, 3019, 2927, 2177, 1643, 1599, 1528, 1216,
1092, 1011 cmK1; 1H NMR (200 MHz, CDCl3) d 3.56–3.78
(m, 5H, 2NCH2 and CH), 6.49 (s, 1H, CH), 7.28–7.66 (m,
7H, ArH), 7.81–7.99 (m, 4H, ArH), 8.48 (bs, 1H, NH); FAB
(MS) 424 (MCC1); C26H18ClN3O (423.89) calcd: C 73.67;
H, 4.28 N, 9.91; found: C, 73.49; H, 4.36; N, 10.01.
1595, 1524, 1435, 1303, 1258, 1025 cmK1 1H NMR
;
(200 MHz, CDCl3): d 3.89 (s, 3H, OCH3), 4.03–4.06 (m,
2H, NCH2), 4.14–4.17 (m, 2H, NCH2), 6.79 (s, 1H, CH),
7.01 (d, JZ8.0 Hz, 2H, ArH), 7.33–7.42 (m, 3H, ArH), 7.89
(s, 1H, ArH), 8.35 (d, JZ8.0 Hz, 2H, ArH), 10.11 (bs, 1H,
NH); FAB (MS) 402 (MCC1); C23H16ClN3O2 (401.84)
calcd: C, 68.74; H, 4.01; N, 10.46; found: C, 68.91; H, 3.91;
N, 10.45.
3.2.5. [5-(4-Bromophenyl)-8-(4-chlorobenzoyl)-2,3-di-
hydro-1H-imidazo[1,2-a]pyridin-7-ylidene]-acetonitrile
(5e). Yields 62%; brown-red solid; mp 123–128 8C dec.; IR
(neat) nmax 3368, 3017, 2925, 2176, 1641, 1599, 1527, 1293,
3.3.3. 8-Chloro-4-(4-fluorophenyl)-11-oxo-1,2,3,11-tetra-
hydro-1,3a-diaza-cyclopenta[a]anthracene-6-carbo-
nitrile (6c). Yields 53%; yellow powder; mp O250 8C; IR
(KBr) nmax 3431, 3000, 2190, 1645, 1597, 1524, 1442, 1227,
1
1216, 1092, 1011 cmK1; H NMR (200 MHz, CDCl3) d
3.60 (s, 1H, CH), 3.83 (m, 4H, 2NCH2), 6.31 (s, 1H, CH),
7.11–7.59 (m, 8H, ArH), 8.50 (bs, 1H, NH); FAB (MS) 453
(MCC1) C22H15BrClN3O (452.73) calcd: C, 58.36; H,
3.34; N, 9.28; found: C, 58.49; H, 3.50; N, 9.11.
1
1085 cmK1; H NMR (300 MHz, CDCl3) d 4.06–4.24 (m,
4H, 2NCH2), 6.74 (s, 1H, CH), 7.21–7.53 (m, 5H, ArH),
7.85 (s, 1H, ArH), 8.28 (d, JZ8.7 Hz, 1H, ArH), 10.01 (bs,
1H, NH); FAB (MS) 390 (MCC1); C22H13ClFN3O
(389.81) calcd: C, 67.79; H, 3.36; N, 10.78; found: C,
67.81; H, 3.46; N, 10.92.
3.2.6. [9-(4-Bromobenzoyl)-6-(4-bromophenyl)-1,2,3,4-
tetrahydro-pyrido[1,2-a]pyrimidin-8-ylidene]-aceto-
nitrile (5f). Yields 64%; brown-red solid; mp 157–162 8C
dec.; IR (neat) nmax 3430, 3016, 2926, 2177, 1644, 1591,
1528, 1216, 1073, 1010 cmK1; 1H NMR (200 MHz, CDCl3)
d 1.98–2.08 (m, 2H, CH2), 3.45–3.54 (m, 5H, 2NCH2 and
CH), 6.32 (s, 1H, CH), 7.23–7.26 (m, 2H, ArH), 7.42–7.49
(m, 4H, ArH), 7.58–7.63 (m, 2H, ArH), 10.94 (bs, 1H, NH);
FAB (MS) 512 (MCC1) C23H17 Br2N3O (511.21) calcd: C,
54.04; H, 3.35; N, 8.22; found: C, 54.21; H, 3.50; N, 8.01.
3.3.4. 8-Chloro-4-naphthalen-1-yl-11-oxo-1,2,3,11-tetra-
hydro-1,3a-diaza-cyclopenta[a]anthracene-6-carbo-
nitrile (6d). Yield 54%; yellow powder; mp O250 8C; IR
(KBr) nmax 3433, 3055, 2193, 1645, 1591, 1523, 1430, 1310,
1256, 1084 cmK1; 1H NMR (200 MHz, CDCl3) d 3.83–4.09
(m, 4H, 2NCH2), 7.02 (s, 1H, CH), 7.31–7.36 (m, 1H, ArH),
7.57–7.72 (m, 5H, ArH), 7.93–8.01 (m, 3H, ArH), 8.38 (d,
JZ8.7 Hz, 1H, ArH), 10.01 (bs, 1H, NH); FAB (MS) 422
(MCC1); C26H16ClN3O (421.88) calcd: C, 74.02; H, 3.82;
N, 9.96; found: C, 74.12; H, 3.92; N, 9.11.
3.2.7. [9-(4-Bromobenzoyl)-6-(4-methylphenyl)-1,2,3,4-
tetrahydro-pyrido[1,2-a]pyrimidin-8-ylidene]-aceto-
nitrile (5g). Yields 65%; brown-red solid; mp 195–200 8C
dec.; IR (neat) nmax 3018, 2927, 2177, 1645, 1590, 1530,
3.3.5. 4-(4-Bromophenyl)-8-chloro-11-oxo-1,2,3,11-
tetrahydro-1,3a-diaza-cyclopenta[a]anthracene-6-
carbonitrile (6e). Yield 62%; yellow powder; mp
O250 8C; IR (KBr) nmax 3330, 2183, 1642, 1593, 1516,
1
1216, 1072, 1010 cmK1; H NMR (200 MHz, CDCl3): d
1.97–2.02 (m, 2H, CH2), 2.41 (s, 3H, CH3), 3.43–3.56 (m,
5H, 2NCH2 and CH), 6.32 (s, 1H, CH), 7.24–7.60 (m, 8H,
ArH), 10.90 (bs, 1H, NH); FAB (MS) 447 (MCC1); C24H20
BrN3O (446.34) calcd: C, 64.58; H, 3.34; N, 9.28; found: C,
64.39; H, 3.49; N, 9.11.
1
1219 cmK1; H NMR (200 MHz, CDCl3) d 4.06–4.23 (m,
4H, 2NCH2), 6.84 (s, 1H, CH), 7.28–7.40 (m, 4H, ArH),
7.67–7.71 (m, 3H, ArH); FAB (MS) 451 (MCC1);
C22H13BrClN3O (450.71) calcd: C, 58.63; H, 2.91; N,
9.32; found: C, 58.71; H, 3.05; N, 9.62.
3.3. General procedure for the synthesis of aza-
[a]anthracenones (6)
3.3.6. 9-Bromo-5-(4-bromophenyl)-12-oxo-1,3,4,12-
tetrahydro-2H-1,4a-diaza-benzo[a]anthracene-7-carbo-
nitrile (6f). Yield 52%; yellow powder; mp O250 8C; IR
A solution of 5 (0.05 mmol) in acetonitrile (10 mL) was
irradiated under stirring for 10 h by 200 W electric bulb. A
yellow solid separated, was filtered and washed with
methanol. The crude product was further purified by column
(KBr) nmax 3435, 2179, 1646, 1600, 1514, 1326, 1207 cmK1
;
1H NMR (300 MHz, CDCl3): d 2.08–2.16 (m, 2H, CH2),

3786
A. Sharon et al. / Tetrahedron 61 (2005) 3781–3787
3.65 (t, JZ6.0 Hz, 2H, NCH2), 3.80 (t, JZ6.0 Hz, 2H,
NCH2), 6.84 (s, 1H, CH), 7.41–7.54 (m, 5H, ArH), 8.09 (s,
1H, ArH), 8.31 (d, JZ9.0 Hz, 1H, ArH), 14.04 (bs, 1H,
NH); FAB (MS) 510 (MCC1); C23H15Br2N3O (509.19)
calcd: C, 54.25; H, 2.97; N, 8.25; found: C, 54.35; H, 2.92;
N, 8.32.
7.45 (d, JZ8.5 Hz, 2H, ArH), 7.67 (d, JZ5.1 Hz, 1H, ArH),
8.49 (d, JZ5.2 Hz, 1H, ArH), 9.42 (s, 1H, ArH); FAB (MS)
369 (MCC1); C22H16N4O2 (368.13) calcd: C, 71.73; H,
4.38; N, 15.21; found: C, 71.81; H, 4.42; N, 15.27.
3.4.4. 12-Oxo-5-phenyl-1,3,4,12-tetrahydro-2H-1,4a,10-
triaza-benzo[a]anthracene-7-carbonitrile (8d). Yield
49%; yellow powder; mp O250 8C; IR (KBr) nmax 3377,
3.3.7. 9-Bromo-12-oxo-5-(4-methylphenyl)-1,3,4,12-
tetrahydro-2H-1,4a-diaza-benzo[a]anthracene-7-carbo-
nitrile (6g). Yield 55%; yellow powder; mp O250 8C; IR
(KBr) nmax 3430, 2193, 1738, 1641, 1598, 1515, 1325,
2926, 2854, 2363, 2184, 1742, 1646, 1507, 1448, 1362 cmK1
;
1H NMR (200 MHz, CDCl3) d 2.07–2.18 (m, 2H, CH2),
3.64–3.66 (m, 2H, NCH2), 3.78–3.84 (m, 2H, NCH2), 6.84
(s,1H, CH), 7.40–7.45 (m, 2H, ArH), 7.52–7.56 (m, 3H,
ArH), 7.65 (d, JZ5.8 Hz, 1H, ArH), 8.57 (s, 1H, ArH), 9.62
(s, 1H, ArH); FAB (MS) 353 (MCC1); C22H16N4O
(352.13) calcd: C, 74.98; H, 4.58; N, 15.90; found: C,
74.91; H, 4.62; N, 15.83.
1
1208 cmK1; H NMR (200 MHz, CDCl3) d 2.07–2.13 (m,
2H, CH2), 2.45 (s, 3H, CH3), 3.63 (t, JZ5.5 Hz, 2H, NCH2),
3.79 (t, JZ5.5 Hz, 2H, NCH2), 6.80 (s, 1H, CH), 7.30–7.46
(m, 5H, ArH), 8.07 (s, 1H, ArH), 8.30 (d, JZ8.74 Hz, 1H,
ArH), 13.81 (bs, 1H, NH); FAB (MS) 445 (MCC1);
C24H18BrN3O (444.32) calcd: C, 64.88; H, 4.08; N, 9.46;
found: C, 65.06; H, 4.22; N, 9.41.
3.4.5. 12-Oxo-5-(4-methylphenyl)-1,3,4,12-tetrahydro-
2H-1,4a,10-triaza-benzo[a]anthracene-7-carbonitrile
(8e). Yield 40%; yellow powder; mp O250 8C; IR (KBr)
3.4. General procedure for the synthesis of triaza-cyclo-
penta[a]anthracene-6-carbonitriles (8) and thieno[3,2-g]-
aza-naphthalenones (9)
nmax 3404, 2832, 2368, 2188, 1635, 1605, 1514, 1362 cmK1
;
1H NMR (200 MHz, CDCl3) d 2.12–2.17 (m, 2H, CH2),
2.47 (s, 3H, CH3), 3.68 (t, JZ5.7 Hz, 2H, NCH2), 3.87 (t,
JZ5.7 Hz, 2H, NCH2), 6.82 (s, 1H, CH), 7.35–7.41 (m, 4H,
ArH), 7.67 (d, JZ5.7 Hz, 1H, ArH), 8.48–8.49 (m, 1H,
ArH), 9.51 (s, 1H, ArH); FAB (MS) 367 (MCC1);
C23H18N4O (366.15) calcd: C, 75.39; H, 4.95; N, 15.29;
found: C, 75.48; H, 5.08; N, 15.34.
A mixture of 2H-pyran-2-one (4, 1 mmol), a-oxoketene
cyclic aminal (3, 1 mmol) and NaH (60% suspension,
2.5 mmol) in dry THF (15 mL) was stirred for 15 h under
light irradiation by 200 W electric bulb. The reaction
mixture was poured onto ice water (50 mL), neutralized
with 10% HCl. The precipitate obtained was filtered,
washed with water (50 mL) and dried. The crude solid
was finally purified on Si-gel column chromatography using
4% methanol in chloroform as eluent.
3.4.6. 5-(4-Bromophenyl)-12-oxo-1,3,4,12-tetrahydro-
2H-1,4a,10-triaza-benzo[a]anthracene-7-carbonitrile
(8f). Yield 55%; yellow powder; mp O250 8C; IR (KBr)
nmax 3404, 2930, 2832, 2368, 2191, 1630, 1590, 1510,
3.4.1. 11-Oxo-4-phenyl-1,2,3,11-tetrahydro-1,3a,9-tri-
aza-cyclopenta[a]anthracene-6-carboxylic acid methyl
ester (8a). Yield 35%; yellow powder; mp O250 8C; IR
(KBr) nmax 3398, 2926, 2370, 1851, 1705, 1657, 1597,
1441 cmK1; 1H NMR (200 MHz, 2 drop CD3OD in CDCl3)
d 3.95 (s, 3H, COOCH3), 4.16 (t, JZ5.6 Hz, 2H, NCH2),
4.35 (t, JZ5.6 Hz, 2H, NCH2), 7.28 (s,1H, CH), 7.51–7.56
(m, 5H, ArH), 8.07 (d, JZ6.0 Hz, 1H, ArH), 8.2 (d, JZ
6.0 Hz, 1H, ArH), 9.24 (s, 1H, ArH); FAB (MS) 372 (MCC
1); C22H17N3O3 (371.13) calcd: C, 71.15; H, 4.61; N, 11.31;
found: C, 71.22; H, 4.73; N, 11.33.
1
1362 cmK1; H NMR (200 MHz, CDCl3) d 2.09–2.14 (m,
2H, CH2), 3.61–3.63 (m, 2H, NCH2), 3.75–3.80 (m, 2H,
NCH2), 6.69 (s, 1H, CH), 7.32 (d, JZ8.3 Hz, 2H, ArH),
7.58 (d, JZ5.8 Hz, 1H, ArH), 7.67 (d, JZ8.3 Hz, 2H, ArH),
8.57 (d, JZ5.8 Hz, 1H, ArH), 9.53 (s, 1H, ArH); FAB (MS)
432 (MCC1); C22H15BrN4O (430.04) calcd: C, 61.27; H,
3.51; N, 12.99; found: C, 61.39; H, 3.74; N, 13.11.
3.4.7. 10-Oxo-4-phenyl-1,2,3,10-tetrahydro-9-thia-1,3a-
diaza-dicyclopenta[a,g]naphthalene-6-carbonitrile (9a).
Yield 35%; yellow powder; mp O250 8C; IR (KBr) nmax
2929, 2832, 2717, 2191, 1628, 1593, 1364 cmK1; 1H NMR
(200 MHz, 2 drops CD3OD in CDCl3) d 4.10–4.26 (m, 4H,
2NCH2), 6.93 (s, 1H, CH), 7.34 (s, 1H, ArH), 7.44–7.57 (m,
5H, ArH), 7.78 (d, JZ5.3 Hz, 1H, ArH); FAB (MS) 344
(MCC1); C20H13N3OS (343.08) calcd: C, 69.95; H, 3.82;
N, 12.24; found: C, 69.86; H, 3.91; N, 12.32.
3.4.2. 11-Oxo-4-phenyl-1,2,3,11-tetrahydro-1,3a,9-
triaza-cyclopenta[a]anthracene-6-carbonitrile (8b).
Yield 43%; yellow powder; mp O250 8C; IR (KBr) nmax
3277, 2831, 2367, 2211, 1630, 1596, 1527, 1363 cmK1; 1H
NMR (200 MHz, 2 drops CD3OD in CDCl3) d 4.16–4.26
(m, 2H, NCH2), 4.69–4.82 (m, 2H, NCH2), 6.93 (s, 1H, CH),
7.52–7.61 (m, 5H, ArH), 7.91 (d, JZ6.2 Hz, 1H, ArH), 8.32
(d, JZ6.2 Hz, 1H, ArH), 9.26 (s, 1H, ArH); FAB (MS) 339
(MCC1); C21H14N4O (338.12) calcd: C, 74.54; H, 4.17; N,
16.56; found: C, 74.67; H, 4.23; N, 16.65.
3.4.8. 4-(4-Methoxyphenyl)-10-oxo-1,2,3,10-tetrahydro-
9-thia-1,3a-diaza-dicyclopenta[a,g]naphthalene-6-
carbonitrile (9b). Yield 51%; yellow powder; mp
O250 8C; IR (KBr) nmax 2936, 2832, 2717, 2363, 2210,
1705, 1648, 1592, 1364 cmK1; 1H NMR (200 MHz, 2 drops
CD3OD in CDCl3) d 3.9 (s, 3H, OCH3), 4.10–4.28 (m, 4H,
2NCH2), 6.90 (s, 1H, CH), 7.05 (d, JZ8.5 Hz, 2H, ArH),
7.42–7.46 (m, 3H, ArH), 7.79 (d, JZ5.3 Hz, 1H, ArH);
FAB (MS) 374 (MCC1); C21H15N3O2S (373.08) calcd:
C, 67.54; H, 4.05; N, 11.25; found: C, 67.69; H, 4.25; N,
11.32.
3.4.3. 4-(4-Methoxyphenyl)-11-oxo-1,2,3,11-tetrahydro-
1,3a,9-triaza-cyclopenta[a]anthracene-6-carbonitrile
(8c). Yield 53%; yellow powder; mp O250 8C; IR (KBr)
nmax 3377, 2926, 2833, 2368, 2186, 1632, 1589, 1362 cmK1
;
1H NMR (200 MHz, 2 drops CD3OD in CDCl3) d 3.76 (s,
3H, OCH3), 4.09–4.18 (m, 2H, NCH2), 4.26–4.30 (m, 2H,
NCH2), 6.83 (s, 1H, CH), 7.07 (d, JZ8.5 Hz, 2H, ArH),

A. Sharon et al. / Tetrahedron 61 (2005) 3781–3787
3787
M. J.; Hacker, M. P. J. Med. Chem. 1994, 37, 828. (b) Faulds,
D.; Balfour, J. A.; Chrisp, P.; Langtry, H. D. Drugs 1999, 41,
400.
3.4.9. 5-(4-Bromophenyl)-11-oxo-1,3,4,11-tetrahydro-
2H-10-thia-1,4a-diaza-cyclopenta[b]phenanthrene-7-
carbonitrile (9c). Yield 48%; yellow powder; mp
O250 8C; IR (KBr) nmax 3424, 2365, 2197, 1635, 1593,
1528, 1351 cmK1; 1H NMR (200 MHz, CDCl3) d 2.07–2.13
(m, 2H, CH2), 3.62 (t, JZ5.8 Hz, 2H, NCH2), 3.77 (t, JZ
5.9 Hz, 2H, NCH2), 6.86 (s, 1H, CH), 7.31 (d, JZ8.3 Hz,
2H, ArH), 7.43 (d, JZ5.3 Hz, 1H, ArH), 7.67 (d, JZ8.3 Hz,
2H, ArH), 7.71 (d, JZ5.3 Hz, 1H, ArH); FAB (MS) 437
(MCC2); C21H14BrN3OS (435.00) calcd: C, 57.81; H,
3.23; N, 9.63; found: C, 57.89; H, 3.33; N, 9.82.
5. (a) Selassie, C. D.; Hansch, C.; Khwaja, T. A. J. Med. Chem.
1990, 33, 1914. (b) Kolata, G. Science 1986, 231, 220–221. (c)
Hill, B. T.; Hosking, L. K.; Shellard, S. A.; Whelan, R. D. H.
Cancer Chemother. Pharmacol. 1989, 23, 140.
6. (a) Warren, J. D.; Lee, V. J.; Angier, R. B. J. Heterocycl.
Chem. 1979, 16, 1617. (b) Birch, A. J.; Butler, D. N.; Siddal,
J. B. J. Chem. Soc. 1964, 2941. (c) Joullie, M. M.;
Duthenpurayil, J. K. J. Heterocycl. Chem. 1969, 6, 697. (d)
Levy, M. R. W.; Joullie, M. M. J. Heterocycl. Chem. 1964, 1,
171. (e) Munshi, J. F.; Joullie, M. M. J. Heterocycl. Chem.
1967, 4, 133.
3.4.10. 11-Oxo-5-(4-methylphenyl)-1,3,4,11-tetrahydro-
2HK10-thia-1,4a-diaza-cyclopenta[b]phenanthrene-7-
carbonitrile (9d). Yield 52%; yellow powder; mp
O250 8C; IR (KBr) nmax 2832, 2379, 2192, 1634, 1586,
1526, 1361 cmK1; 1H NMR (200 MHz, CDCl3) d 2.05–2.14
(m, 2H, CH2), 2.46 (s, 3H, CH3), 3.82–3.87 (m, 4H,
2NCH2), 6.84 (s, 1H, CH), 7.20–7.38 (m, 4H, ArH), 7.41 (d,
JZ5.3 Hz, 1H, ArH), 7.46 (d, JZ5.3 Hz, 1H, ArH); FAB
(MS) 372 (MCC1); C22H17N3OS (371.11) calcd: C, 71.14;
H, 4.61; N, 11.31; found: C, 71.16; H, 4.72; N, 11.45.
7. Raudnitz, H. Ber. Dtxch. Chem. Ges. 1929, 62, 509.
8. Schofield, K.; Wright, D. E. J. Chem. Soc. 1965, 6074.
9. Ram, V. J.; Srivastava, P. Curr. Org. Chem. 2001, 5, 571.
10. (a) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A. J. Chem.
Res (s) 1991, 98. (b) Ram, V. J.; Verma, M.; Hussaini, F. A.;
Shoeb, A. Liebigs Ann. Chem. 1991, 1229. (c) Ram, V. J.;
Srivastava, P.; Goel, A. Tetrahedron 2003, 59, 7141. (d)
Sharon, A.; Maulik, P. R.; Vithana, C.; Ohashi, Y.; Ram, V. J.
Eur. J. Org. Chem. 2004, 886. (e) Ram, V. J.; Goel, A.
Tetrahedron Lett. 1996, 37, 93.
Acknowledgements
11. Zhan-Jiang, L.; Yang, Q.; Chen, X.-M.; Huang, Z.-T. Synthesis
1994, 231.
Ashoke Sharon thanks CSIR, New Delhi, India for Senior
Research Fellowship. VJR and RP are thankful to ICMR,
New Delhi for financial support. We thank to SAIF, CDRI,
Lucknow for providing spectroscopic and analytical data.
12. Crystal data of 6f: C23H15Br2N3O$CHCl3, MZ628.57,
triclinic, space group: P-1, aZ7.796(1), bZ10.726(1), cZ
˚
15.686(1) A, aZ83.14(1), bZ79.16(1), gZ73.58(1), VZ
3
1232.7(2) A , TZ293 K, ZZ2, mZ3.64 mmK1, F(000)Z
˚
620.0, R1Z0.1072 for 1919 FoO4sig(Fo) and 0.2226 for all
4249 data. CCDC No. 260828 contains the supplementary
crystallographic data. These data can be obtained free of
charge from www.ccdc.cam.uk/conts/retrieving.html [or from
the Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge, CB2 1EZ, UK; fax: (internat.) C44 1223/336 033;
E-mail: deposit@ccdc.cam.ac.uk]. Programs: XSCANS [Sie-
mens Analytical X-ray Instrument Inc.: Madison, Wisconsin,
USA 1996], SHELXTL-NT [Bruker AXS Inc.: Madison,
Wisconsin, USA 1997].
References and notes
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2. Frame, M. C. Biochem. Biophys. Acta 2002, 1602, 114.
3. Reinhert, G.; Hilfiker, R. (Ciba-Geigy A.-G., Switz). Ger
Offen, 1996, 8pp. Ceden: GWXXBX DE 19613251 A
1#19961010.
13. Cuppen, Th. J. H. M. ; Laarhoven, W. H. J. Am. Chem. Soc.
1972, 94, 5914.
4. (a) Krapcho, A. P.; Petry, M. E.; Getahun, Z.; Landi, J. J.;
Stallman, J., Jr.; Polsenberg, J. F.; Gallagher, C. E.; Maresch,