An innovative approach to the synthesis of annelated [a]diaza-anthracenones through tandem cyclization

Article abstract of DOI:10.1016/j.tetlet.2004.06.015

An innovative route for the synthesis of a novel class of 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a-diazacyclopenta[a]anthracene-6- carbonitriles 5a-h and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-diazabenzo[a] anthracene-7-carbonitriles 5i-k has been developed by ring transformation of suitably functionalized 2H-pyran-2-ones 1 with α-oxoketene cyclic aminals 2 to give compounds 4 followed by photo-induced cyclization.

Full text of DOI:10.1016/j.tetlet.2004.06.015

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5815–5818
An innovative approach to the synthesis of annelated
[a]diaza-anthracenones through tandem cyclizationq
Ashoke Sharon,a Prakas R. Maulik,a Raja Royb and Vishnu Ji Ramc,*
aMolecular and Structural Biology Division, Central Drug Research Institute, Lucknow 226001, India
bSophisticated Analytical Instrument Facility, Central Drug Research Institute, Lucknow 226001, India
cMedicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 21 April 2004; revised 26 May 2004; accepted 3 June 2004
Abstract—An innovative route for the synthesis of
a novel class of 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a-diazacyclo-
penta[a]anthracene-6-carbonitriles 5a–h and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-diazabenzo[a]anthracene-7-carbonitriles
5i–k has been developed by ring transformation of suitably functionalized 2H-pyran-2-ones 1 with a-oxoketene cyclic aminals 2 to
give compounds 4 followed by photo-induced cyclization.
Ó 2004 Elsevier Ltd. All rights reserved.
Polyheterocyclic quinone1 [(PHQ (Fig. 1) systems are
known to display diverse pharmacological and indus-
trial applications especially as anticancer agents,2 and
vat dyes.3 The chemistry and therapeutic importance of
annelated [a]azaanthraquinones have been explored
extensively, but the synthesis and pharmacology of
bridgehead annelated [a]diazaanthracenone (DAA)
(Fig. 1) are unexplored so far.
none and 1-amino-2-(1-amino-2-benzoylvinyl)-9,10-
anthraquinone in piperidine separately. PHQs have been
synthesized6 by Michael addition of indole to 2,5,8-
quinolinetriones followed by Diels–Alder cycloaddition
in good yield. Nonannelated azaanthraquinones have
been obtained either by Diels–Alder reaction of azanaphth-
aquinone with an appropriate diene7 or by classical
Friedel–Crafts reaction8 or by oxidation of 9,10-dihy-
droazaanthracene.9 Bridgehead annelated [a]diazaanth-
racenones (DAAs) have not been reported so far.
Fused heterocyclic anthraquinones have been pre-
pared4;5 by heating 1-amino-2-ethynyl-9,10-anthraqui-
The presence of the 2H-pyran-2-one 1 unit in many
natural products and its suitability for ring transfor-
mation reactions have led to its exploitation as a syn-
thon for generating molecular diversity.10 Herein we
report a short efficient access to fused anthracenone
derivatives 5 through ring transformation reactions of
suitably functionalized 2H-pyran-2-ones 1 with a-oxo-
ketene cyclic aminals 2 followed by photocyclization.
O
2
R
N
O
O
X
HN (CH )
2 n
CH
N
O
O
CH
3
3
R
N
O
Ar
O
2
N
R
1
R
Our strategy to synthesize 4-aryl-11-oxo-1,2,3,11-tetra-
hydro-1,3a-diazacyclopenta[a]anthracene-6-carbonitr-
iles 5a–h and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-
1,4a-diazabenzo[a]anthracene-7-carbonitriles 5i–k was
based on the reaction of 6-aryl-4-methylsulfanyl-2-oxo-
2H-pyran-3-carbonitriles11 1 with a-oxo-ketene cyclic
aminals 2, obtained12 from the reaction of a-oxo-
ketenedithioacetal and diaminoalkanes (Scheme 1).
Thus, stirring an equimolar mixture of 1, 2 and
powdered KOH in dry DMF for 24 h at ambient
DAA
PHQ
Figure 1. Chemical structure of polyheterocyclic quinones (PHQs) and
diazaanthracenones (DAAs).
Keywords: Photocyclization; X-ray diffraction; Ring transformation
reactions; Reaction mechanism.
q CDRI communication no: 6523.
* Corresponding author. Tel.: +91-522-2212411-4381; fax: +91-522-
2223405; e-mail: vjiram@yahoo.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.015

5816
A. Sharon et al. / Tetrahedron Letters 45 (2004) 5815–5818
such substituents enhance the electrophilicity of C6 of
Ar'
SCH3
CN
the pyran ring to nucleophilic attack. 2H-Pyran-2-ones 1
can be considered as a cyclic ketene hemithioacetal,
which is prone to nucleophilic attack at C6 due to ex-
tended conjugation. a-Oxoketene cyclic aminals 2, have
three nucleophilic centres, two secondary amines and a
vinylic carbon adjacent to the carbonyl function. Thus
possibilities for the formation of two intermediates 3 or
4 exist, depending upon the initial participation of either
of the nitrogen or carbon nucleophilic centres. Reaction
through intermediate 3 was ruled out on the basis of the
structure of the isolated photocyclized product 5, which
is only available from intermediate 4. Further photo-
irradiation of intermediate 4 in acetonitrile with a 200 W
electric bulb provided cyclized product 5 in moderate
yield. In cases where photocyclized products precipi-
tated, they were filtered off and recrystallized from a
chloroform–methanol mixture, or purified by Si-gel
column chromatography. The UV spectrum of a freshly
prepared 0.01 mM solution of 4 in DMSO showed an
absorption band at 435 nm, which completely disap-
peared after irradiation for 2 h with the appearance of a
new absorption maximum at 385 nm (Fig. 2).
O
+
HN NH
(CH2)n
Ar
O
O
2
H3CS
H3CS
1
Path A X
Path B
O
O
CN
Ar'
O
CN
O
H3CS
HN
O
(CH2)n
N
H
N
NH
Ar
Ar'
Ar
(CH2)n
O
N
Ar'
C
H
N
O
C N
HN
H
N
H3CS
Ar
(CH2)n
Ar'
(CH2)n
N
H
C
H
Ar
Ar'
N
O
O
H3CS
N
O
N
C
N
N
Ar
(CH2)n
-CH3SH
H3CS
(CH2)n
A free radical mechanism for the photochemical trans-
formation of 4 was ruled out on the basis of the isolation
of product 5 even in the presence of TEMPO free rad-
ical. Thus, the reaction possibly proceeds through a
photochemically allowed conrotatory cyclization13 fol-
lowed by aerial oxidation of a dihydro intermediate to
yield 5. A plausible mechanism for this reaction involves
nucleophilic attack of the secondary amine at C6 of the
pyran ring with ring opening followed by decarboxyl-
ation and recyclization, involving the vinylic carbon and
C4 of the pyran ring liberating methyl mercaptan to
yield 4 (Scheme 1). The stereoselective formation of
intermediate 4 in this reaction is possibly due to either
strong intramolecular hydrogen bonding between the
NH and C@O functionalities or steric hindrance, which
plays an important role in restricting the rotation of the
aroyl group and enforces the required E geometry.
Intermediates 4 isolated from this reaction were char-
acterized by IR, NMR and mass spectrometry14 as (E)-
2-(8-aroyl-5-aryl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-
7-ylidene)acetonitrile (4, n ¼ 1) and (E)-2-(9-aroyl-6-
aryl-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrimidin-8-yl-
idene)acetonitrile (4, n ¼ 2). The proton NMR spectrum
of 4e demonstrated two CH singlets at 6.33 and
N
H
R
HN (CH2)n
N
Ar
Ar'
O
NC
-CH3SH
Ar
NC
4
hν
N
(CH2)n
O HN (CH2)n
N
Ar
Ar'
N
H
O
R
Ar
3
CN
5
Ar' = C6H4R
Yield
4
5
n
4/5
Ar
R
H
H
H
Cl
a
b
c
d
e
f
g
h
i
4-ClC6H4
4-BrC6H4
C6H5
C6H5
4-CH3OC6H4 Cl
4-FC6H4
1-naphthyl
4-BrC6H4
C6H5
4-BrC6H4
4-CH3C6H4
1
1
1
1
1
1
1
1
2
2
2
65 42
57 44
66 52
58 49
62 48
51 41
65 53
55 52
64 53
55 46
61 54
Cl
Cl
Cl
Br
Br
Br
j
k
Scheme 1. Proposed mechanism for the formation of 5.
temperature and usual work-up led to 5 directly but in
very poor yield (5%). Thus, attempts were made to
isolate any intermediates to understand the course of the
reaction as well as to improve the yield. The interme-
diate 4 was synthesized from the reaction of 1 and 2 and
purified in the absence of direct light in ꢀ60% yield. The
photocyclization of 4 in acetonitrile yielded 5 in ꢀ50%
yield.
2.5
2
Intermediate (4d)
1.5
Product (5d)
1
0.5
0
300 350 400 450 500 550 600 650 700
The nature of the ring substituents present at positions 3
and 4 of the pyran ring greatly influences the course of
these reactions. An electron withdrawing substituent,
especially at position 3, is an essential requirement, as
Wavelength (nm)
Figure 2. Absorption maxima of intermediate 4d (435 nm) and product
5d (385 nm) after irradiation (200 W electric bulb) for 2 h.

A. Sharon et al. / Tetrahedron Letters 45 (2004) 5815–5818
5817
5. Barabanov, I. I.; Fedenok, L. G.; Polyakov, N. E.;
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~
6. Lopez-Alvarado, P.; Alonso, M. A.; Avendano, C.;
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J. Heterocycl. Chem. 1967, 4, 133–136.
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C. E.; Maresch, M. J.; Hacker, M. P.; Giuliani, F. C.
J. Med. Chem. 1994, 37, 828–837.
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Ohashi, Y.; Ram, V. J. Eur. J. Org. Chem. 2004, 886–893;
(c) Ram, V. J.; Goel, A. Tetrahedron Lett. 1996, 37, 93–96;
(d) Saxena, A. S.; Goel, A.; Ram, V. J. Synlett 2002, 1491–
1492.
11. (a) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A.
J. Chem. Res. (S) 1991, 98–99; (b) Ram, V. J.; Verma, M.;
Hussaini, F. A.; Shoeb, A. Liebigs Ann. Chem. 1991, 1229–
1231.
12. (a) Li, Z.-J.; Yang, Q.; Chen, X.-M.; Huang, Z.-T.
Synthesis 1999, 231–233; (b) Huang, Z.-T.; Liu, Z.-R.
Chem. Ber. 1989, 122, 95–100.
Figure 3. ORTEP diagram of 5a showing the X-ray molecular struc-
ture at the 50% probability level.
3.59 ppm, a methyl singlet at 3.83 ppm, a set of methyl-
ene protons as a multiplet centred at 3.86 ppm, two sets
of ortho coupled doublets at 7.34 and 7.57 ppm and a
broad singlet at 8.49 ppm for the NH proton. The high
field shift of the vinylic proton at 3.59 ppm and its 13C
chemical shift at 72.9 ppm can be attributed to the
shielding effect of the carbonyl and nitrile functional-
ities. The structure of the photocyclized products 5 were
confirmed spectroscopically14 and also through a single
crystal X-ray diffraction analysis for product 5a (Fig.
3).15
The X-ray structure revealed that two rotamers 47.1° (2)
and 77.4° (2) are present in one asymmetric unit.
Rotamers arise due to free rotation along the aryl–aryl
bond.
13. Cuppen, Th. J. H. M.; Laarhoven, W. H. J. Am. Chem.
Soc. 1972, 94, 5914–5915.
14. Typical procedure for 4: A mixture of 2H-pyran-2-one 1,
(1 mmol), oxoketene cyclic aminal 2 (1 mmol) and NaH
(60% suspension, 2.5 mmol) in dry THF (20 mL) was
stirred for 2 h at 5–10 °C in the dark. After additional
stirring for another 10 h at 20–25 °C, the reaction mixture
was poured into ice-water and neutralized with 10% HCl.
The separated solid was filtered, washed with water and
dried. The reaction was carried out in the dark to prevent
photocyclization. The crude solid was further purified by
column chromatography using 50% hexane–CHCl3) as
eluent in the dark. Compound 4e: Yield 250 mg (62%); mp:
194–196 °C (dec.); IR (neat): m ¼ 3353, 3019, 2927, 2856,
In summary, our methodology provides a concerted
approach to the synthesis of fused heterocyclic systems
in two-steps using readily available starting materials
under mild conditions. It also opens an efficient syn-
thetic route for the synthesis of complex aza hetero-
cycles.
Acknowledgements
1
2175, 1640, 1597, 1529, 1295, 1216, 1091, 1013 cmꢁ1; H
NMR (300 MHz, CDCl3): d ¼ 3:58 (s, 1H, CH), 3.83–3.89
(m, 7H, OCH3 and 2NCH2), 6.32 (s, 1H, CH), 6.95–6.98
(d, J ¼ 8:7 Hz, 2H, ArH), 7.32–7.39 (m, 4H, ArH), 7.56–
7.59 (d, J ¼ 8:4 Hz, 2H, ArH), 8.49 (br s, 1H, NH); 13C
NMR (75 MHz, CDCl3): d ¼ 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 (Mþþ1). Typical procedure for 5: A
solution of 4 (0.05 mmol) in acetonitrile was irradiated for
10 h with a 200 W electric bulb with stirring. A yellow solid
separated which was filtered and washed with methanol.
The crude product was further purified by column
chromatography using 1% methanol in chloroform as
eluent. Compound 5h: Yield 135 mg (52%); mp: >250 °C;
IR (neat): m ¼ 3330, 2183, 1642, 1593, 1516, 1219 cmꢁ1; 1H
NMR (200 MHz, CDCl3): d ¼ 4:06–4:23 (m, 4H, 2NCH2),
6.84 (s, 1H, CH), 7.28–7.40 (m, 4H, ArH), 7.67–7.71 (m,
2H, ArH), 7.91 (br s, 1H, ArH); FAB (MS) 451 (Mþþ1);
C22H13BrClN3O (450.71) calcd C 58.63, H 2.91, N 9.32;
found C 58.71, H 3.05, N 9.62.
A.S. thanks CSIR, New Delhi, India for a Senior
Research Fellowship. The authors thank SAIF, CDRI,
Lucknow for providing spectroscopic and analytical
data.
References and notes
1. Middleton, R. W.; Parrick, J. In The Chemistry of
Quinonoid Compounds; Patai, S., Rappoport, Z., Eds.;
John Wiley and Sons: Chichester, 1988; Vol. 2, p 1019.
2. (a) Phillips, R. M.; Naylor, M. A.; Jaffar, M.; Daughty, S.
W.; Everett, S. A.; Breen, A. G.; Chodry, G. A.; Stratford,
I. J. J. Med. Chem. 1999, 42, 4071–4080; (b) Schulz, W.;
Skibo, E. B. J. Med. Chem. 2000, 43, 629–638; (c) Lee, K.
H. Med. Res. Rev. 1999, 19, 569–596; (d) Skibo, E. B.
Curr. Med. Chem. 1996, 2, 900–931.
3. Reinhert, G.; Hilfiker, R. (Ciba-Geigy, A.-G.; Switz). Ger
Offen (1996), pp 8, Ceden: GWXXBX DE 19613251 A 1#
19961010.
4. Piskunov, A. V.; Shvartsberg, M. S. Mendeleev Commun.
1995, 155–156.
15. Crystal data of 5a: C22H14Cl1N3O1, M ¼ 371:81, ortho-
rhombic, space group Pbca, a ¼ 15:978ð2Þ, b ¼ 17:408ð2Þ,
3
ꢁ
ꢁ
c ¼ 25:366ð2Þ A, V ¼ 7055:4ð13Þ A , T ¼ 293 K, Z ¼ 8,
l ¼ 0:23 mmꢁ1, R1 ¼ 0:0804 for 1644 Fo >4 sig(Fo) and

5818
A. Sharon et al. / Tetrahedron Letters 45 (2004) 5815–5818
0.3330 for all 6204 data. CCDC 233580 contains the
Fax: (internat.) +44-1223/336-033; E-mail: deposit@ccdc.
cam.ac.uk]. Programs: XSCANS [Siemens Analytical X-ray
Instrument Inc.: Madison, Wisconsin, USA 1996], SHEL-
XTL-NT [Bruker AXS Inc.: Madison, Wisconsin, USA
1997].
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 Centre, 12 Union Road, Cambridge, CB2 1EZ, UK;